Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds

ABSTRACT

The present invention provides methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds, as well as methods of treating, preventing or ameliorating symptoms associated with such diseases. Specific examples of autoimmune diseases that can be treated or prevented with the compounds include rheumatoid arthritis and/or its associated symptoms, systemic lupus erythematosus and/or its associated symptoms and multiple sclerosis and/or its associated symptoms.

1. CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.16/360,958, filed on Mar. 21, 2019, which is a continuation of U.S.application Ser. No. 15/468,467, filed on Mar. 24, 2017, which is acontinuation of U.S. application Ser. No. 13/442,480 filed Apr. 9, 2012which is a continuation of U.S. application Ser. No. 10/903,263 filedJul. 30, 2004, which claims benefit under 35 U.S.C. § 119(e) toapplication Ser. No. 60/491,641, filed Jul. 30, 2003, Ser. No.60/531,598, filed Dec. 19, 2003 and Ser. No. 60/572,246, filed May 18,2004, the specification, abstract, claims, and drawings of each of whichare hereby incorporated by reference in their entirety into the presentspecification.

2. FIELD OF THE INVENTION

The present invention relates generally to 2,4-pyrimidinediaminecompounds, pharmaceutical compositions comprising the compounds,intermediates and synthetic methods of making the compounds and methodsof using the compounds and compositions in a variety of contexts, suchas in the treatment or prevention of autoimmune diseases and/or thesymptoms associated therewith.

3. BACKGROUND OF THE INVENTION

Crosslinking of Fc receptors, such as the high affinity receptor for IgE(FεRI) and/or the high affinity receptor for IgG (FcγRI) activates asignaling cascade in mast, basophil and other immune cells that resultsin the release of chemical mediators responsible for numerous adverseevents. For example, such crosslinking leads to the release of preformedmediators of Type I (immediate) anaphylactic hypersensitivity reactions,such as histamine, from storage sites in granules via degranulation. Italso leads to the synthesis and release of other mediators, includingleukotrienes, prostaglandins and platelet-activating factors (PAFs),that play important roles in inflammatory reactions. Additionalmediators that are synthesized and released upon crosslinking Fcreceptors include cytokines and nitric oxide.

The signaling cascade(s) activated by crosslinking Fc receptors such asFcεRI and/or FcγRI comprises an array of cellular proteins. Among themost important intracellular signal propagators are the tyrosinekinases. And, an important tyrosine kinase involved in the signaltransduction pathways associated with crosslinking the FcεRI and/orFcγRI receptors, as well as other signal transduction cascades, is Sykkinase (see Valent et al., 2002, Intl. J. Hematol. 75(4):257-362 forreview).

As the mediators released as a result of FcεRI and FcγRI receptorcross-linking are responsible for, or play important roles in, themanifestation of numerous adverse events, the availability of compoundscapable of inhibiting the signaling cascade(s) responsible for theirrelease would be highly desirable. Moreover, owing to the critical rolethat Syk kinase plays these and other receptor signaling cascade(s), theavailability of compounds capable of inhibiting Syk kinase would also behighly desirable.

4. SUMMARY OF THE INVENTION

In one aspect, the present invention provides novel2,4-pyrimidinediamine compounds that, as will be discussed in moredetail below, have myriad biological activities. The compounds generallycomprise a 2,4-pyrimidinediamine “core” having the following structureand numbering convention:

The compounds of the invention are substituted at the C2 nitrogen (N2)to form a secondary amine and are optionally further substituted at oneor more of the following positions: the C4 nitrogen (N4), the C5position and/or the C6 position. When substituted at N4, the substituentforms a secondary amine. The substituent at N2, as well as the optionalsubstituents at the other positions, may range broadly in character andphysico-chemical properties. For example, the substituent(s) may be abranched, straight-chained or cyclic alkyl, a branched, straight-chainedor cyclic heteroalkyl, a mono- or polycyclic aryl a mono- or polycyclicheteroaryl or combinations of these groups. These substituent groups maybe further substituted, as will be described in more detail below.

The N2 and/or N4 substituents may be attached directly to theirrespective nitrogen atoms, or they may be spaced away from theirrespective nitrogen atoms via linkers, which may be the same ordifferent. The nature of the linkers can vary widely, and can includevirtually any combination of atoms or groups useful for spacing onemolecular moiety from another. For example, the linker may be an acyclichydrocarbon bridge (e.g, a saturated or unsaturated alkyleno such asmethano, ethano, etheno, propano, prop[1]eno, butano, but[1]eno,but[2]eno, buta[1,3]dieno, and the like), a monocyclic or polycyclichydrocarbon bridge (e.g., [1,2]benzeno, [2,3]naphthaleno, and the like),a simple acyclic heteroatomic or heteroalkyldiyl bridge (e.g., —O—, —S—,—S—O—, —NH—, —PH—, —C(O)—, —C(O)NH—, —S(O)—, —S(O)₂—, —S(O)NH—,—S(O)₂NH—, —O—CH₂—, —CH₂—O—CH₂—, —O—CH═CH—CH₂—, and the like), amonocyclic or polycyclic heteroaryl bridge (e.g., [3,4]furano, pyridino,thiopheno, piperidino, piperazino, pyrazidino, pyrrolidino, and thelike) or combinations of such bridges.

The substituents at the N2, N4, C5 and/or C6 positions, as well as theoptional linkers, may be further substituted with one or more of thesame or different substituent groups. The nature of these substituentgroups may vary broadly. Non-limiting examples of suitable substituentgroups include branched, straight-chain or cyclic alkyls, mono- orpolycyclic aryls, branched, straight-chain or cyclic heteroalkyls, mono-or polycyclic heteroaryls, halos, branched, straight-chain or cyclichaloalkyls, hydroxyls, oxos, thioxos, branched, straight-chain or cyclicalkoxys, branched, straight-chain or cyclic haloalkoxys,trifluoromethoxys, mono- or polycyclic aryloxys, mono- or polycyclicheteroaryloxys, ethers, alcohols, sulfides, thioethers, sulfanyls(thiols), imines, azos, azides, amines (primary, secondary andtertiary), nitriles (any isomer), cyanates (any isomer), thiocyanates(any isomer), nitrosos, nitros, diazos, sulfoxides, sulfonyls, sulfonicacids, sulfamides, sulfonamides, sulfamic esters, aldehydes, ketones,carboxylic acids, esters, amides, amidines, formadines, amino acids,acetylenes, carbamates, lactones, lactams, glucosides, gluconurides,sulfones, ketals, acetals, thioketals, oximes, oxamic acids, oxamicesters, etc., and combinations of these groups. Substituent groupsbearing reactive functionalities may be protected or unprotected, as iswell-known in the art.

In one illustrative embodiment, the 2,4-pyrimidinediamine compounds ofthe invention are compounds according to structural formula (I):

including salts, hydrates, solvates and N-oxides thereof, wherein:

L¹ and L² are each, independently of one another, selected from thegroup consisting of a direct bond and a linker;

R² and R⁴ are described infra;

R⁵ is selected from the group consisting of R⁶, (C1-C6) alkyl optionallysubstituted with one or more of the same or different R⁸ groups, (C1-C4)alkanyl optionally substituted with one or more of the same or differentR⁸ groups, (C2-C4) alkenyl optionally substituted with one or more ofthe same or different R⁸ groups and (C2-C4) alkynyl optionallysubstituted with one or more of the same or different R⁸ groups;

each R⁶ is independently selected from the group consisting of hydrogen,an electronegative group, —OR^(d), —SR^(d), (C1-C3) haloalkyloxy,(C1-C3) perhaloalkyloxy, —NR^(c)R^(c), halogen, (C1-C3)haloalkyl,(C1-C3)

perhaloalkyl, —CF₃, —CH₂CF₃, —CF₂CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂,—N₃, —S(O)R^(d), —S(O)₂R^(d), —S(O)₂OR^(d), —S(O)NR^(c)R^(c),—S(O)₂NR^(c)R^(c), —OS(O)R^(d), —OS(O)₂R^(d), —OS(O)₂OR^(d),—OS(O)NR^(c)R^(c), —OS(O)₂NR^(c)R^(c), —C(O)R^(d), —C(O)OR^(d),—C(O)NR^(c)R^(c), —C(NH)NR^(c)R^(c), —OC(O)R^(d), —SC(O)R^(d),—OC(O)OR^(d), —SC(O)OR^(d), —OC(O)NR^(c)R^(c), —SC(O)NR^(c)R^(c),—OC(NH)NR^(c)R^(c), —SC(NH)NR^(c)R^(c), —[NHC(O)]_(n)R^(d),—[NHC(O)]_(n)OR^(d), —[NHC(O)]_(n)NR^(c)R^(c) and—[NHC(NH)]_(n)NR^(c)R^(c), (C5-C10) aryl optionally substituted with oneor more of the same or different R⁸ groups, phenyl optionallysubstituted with one or more of the same or different R⁸ groups,(C6-C16) arylalkyl optionally substituted with one or more of the sameor different R⁸ groups, 5-10 membered heteroaryl optionally substitutedwith one or more of the same or different R⁸ groups and 6-16 memberedheteroarylalkyl optionally substituted with one or more of the same ordifferent R⁸ groups;

R⁸ is selected from the group consisting of R^(a), R^(b), R^(a)substituted with one or more of the same or different R^(a) or R^(b),—OR^(a) substituted with one or more of the same or different R^(a) orR^(b), —B(OR^(a))₂, —B(NR^(c)R^(c))₂, —(CH₂)_(m)—R^(b),—(CHR^(a))_(m)—R^(b), —O—(CH₂)_(m)—R^(b), —S—(CH₂)_(m)—R^(b),—O—CHR^(a)R^(b), —O—CR^(a)(R^(b))₂, —O—(CHR^(a))_(m)—R^(b),—O—(CH₂)_(m)CH[(CH₂)_(m)R^(b)]R^(b), —S—(CHR^(a))_(m)—R^(b),—C(O)NH—(CH₂)_(m)R^(b), —C(O)NH—(CHR^(a))_(m)—R^(b), —O—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b), —S—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b),—O—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b),—S—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b), —NH—(CH₂)_(m)—R^(b),—NH—(CHR^(a))_(m)R^(b), —NH[(CH₂)_(m)R^(b)], —N[(CH₂)_(m)R^(b)]₂,—NH—C(O)—NH—(CH₂)_(m)—R^(b), —NH—C(O)—(CH₂)_(m)—CHR^(b)R^(b) and—NH—(CH₂)_(m)—C(O)—NH—(CH₂)_(m)—R^(b);

each R^(a) is independently selected from the group consisting ofhydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11)cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl,piperazinyl, homopiperazinyl, piperidinyl, 4-11 memberedcycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 memberedheteroarylalkyl;

each R^(b) is a suitable group independently selected from the groupconsisting of ═O, —OR^(d), (C1-C3) haloalkyloxy, —OCF₃, ═S, —SR^(d),═NR^(d), ═NOR^(d), —NR^(c)R^(c), halogen, —CF₃, —CN, —NC, —OCN, —SCN,—NO, —NO₂,

═N₂, —N₃, —S(O)R^(d), —S(O)₂R^(d), —S(O)₂OR^(d), —S(O)NR^(c)R^(c),—S(O)₂NR^(c)R^(c), —OS(O)R^(d), —OS(O)₂R^(d), —OS(O)₂OR^(d),—OS(O)₂NR^(c)R^(c), —C(O)R^(d), —C(O)OR^(d), —C(O)NR^(c)R^(c),—C(NH)NR^(c)R^(c), —C(NR^(a))NR^(c)R^(c), —C(NOH)R^(a),—C(NOH)NR^(c)R^(c), —OC(O)R^(d), —OC(O)OR^(d), —OC(O)NR^(c)R^(c),—OC(NH)NR^(c)R^(c), —OC(NR^(a))NR^(c)R^(c), —[NHC(O)]_(n)R^(d),—[NR^(a)C(O)]_(n)R^(d), —[NHC(O)]_(n)OR^(d), —[NR^(a)C(O)]_(n)OR^(d),—[NHC(O)]_(n)NR^(c)R^(c), —[NR^(a)C(O)]_(n)NR^(c)R^(c),—[NHC(NH)]_(n)NR^(c)R^(c) and —[NR^(a)C(NR^(a))]_(n)NR^(c)R^(c);

each R^(c) is independently a protecting group or R^(a), or,alternatively, each R^(c) is taken together with the nitrogen atom towhich it is bonded to form a 5 to 8-membered cycloheteroalkyl orheteroaryl which may optionally include one or more of the same ordifferent additional heteroatoms and which may optionally be substitutedwith one or more of the same or different R^(a) or suitable R^(b)groups;

each R^(d) is independently a protecting group or R^(a);

each m is independently an integer from 1 to 3; and

each n is independently an integer from 0 to 3.

In one embodiment, R⁵ is F and R⁶ is hydrogen.

In another aspect, the present invention provides prodrugs of the2,4-pyrimidinediamine compounds. Such prodrugs may be active in theirprodrug form, or may be inactive until converted under physiological orother conditions of use to an active drug form. In the prodrugs of theinvention, one or more functional groups of the 2,4-pyrimidinediaminecompounds are included in promoieties that cleave from the moleculeunder the conditions of use, typically by way of hydrolysis, enzymaticcleavage or some other cleavage mechanism, to yield the functionalgroups. For example, primary or secondary amino groups may be includedin an amide promoiety that cleaves under conditions of use to generatethe primary or secondary amino group. Thus, the prodrugs of theinvention include special types of protecting groups, termed“progroups,” masking one or more functional groups of the2,4-pyrimidinediamine compounds that cleave under the conditions of useto yield an active 2,4-pyrimidinediamine drug compound. Functionalgroups within the 2,4-pyrimidinediamine compounds that may be maskedwith progroups for inclusion in a promoiety include, but are not limitedto, amines (primary and secondary), hydroxyls, sulfanyls (thiols),carboxyls, carbonyls, phenols, catechols, diols, alkynes, phosphates,etc. Myriad progroups suitable for masking such functional groups toyield promoieties that are cleavable under the desired conditions of useare known in the art. All of these progroups, alone or in combinations,may be included in the prodrugs of the invention. Specific examples ofpromoieties that yield primary or secondary amine groups that can beincluded in the prodrugs of the invention include, but are not limitedto amides, carbamates, imines, ureas, phosphenyls, phosphoryls andsulfenyls. Specific examples of promoieties that yield sulfanyl groupsthat can be included in the prodrugs of the invention include, but arenot limited to, thioethers, for example S-methyl derivatives (monothio,dithio, oxythio, aminothio acetals), silyl thioethers, thioesters,thiocarbonates, thiocarbamates, asymmetrical disulfides, etc. Specificexamples of promoieties that cleave to yield hydroxyl groups that can beincluded in the prodrugs of the invention include, but are not limitedto, sulfonates, esters and carbonates. Specific examples of promoietiesthat yield carboxyl groups that can be included in the prodrugs of theinvention included, but are not limited to, esters (including silylesters, oxamic acid esters and thioesters), amides and hydrazides.

In one illustrative embodiment, the prodrugs of the invention arecompounds according to structural formula (I) in which the protectinggroup of R^(c) and R^(d) is a progroup.

In another illustrative embodiment, the prodrugs of the invention arecompounds according to structural formula (II):

including salts, hydrates, solvates and N-oxides thereof, wherein:

R², R⁴, R⁵, R⁶, L¹ and L² are as previously defined for structuralformula (I);

R^(2b) is a progroup;

R^(4b) is progroup or an alkyl group, e.g., methyl, and as furtherdefined by the examples.

In another aspect, the present invention provides compositionscomprising one or more compounds and/or prodrugs of the invention and anappropriate carrier, excipient or diluent. The exact nature of thecarrier, excipient or diluent will depend upon the desired use for thecomposition, and may range from being suitable or acceptable forveterinary uses to being suitable or acceptable for human use.

In still another aspect, the present invention provides intermediatesuseful for synthesizing the 2,4-pyrimidinediamine compounds and prodrugsof the invention. In one embodiment, the intermediates are4-pyrimidineamines according to structural formula (III):

including salts, hydrates, solvates and N-oxides thereof, wherein R⁴,R⁵, R⁶ and L² are as previously defined for structural formula (I); LGis a leaving group such as, for example, —S(O)₂Me, —SMe or halo (e.g.,F, Cl, Br, I); and R^(4c) is hydrogen, a progroup, an alkyl group or asdescribed herein.

In another embodiment, the intermediates are 2-pyrimidineaminesaccording to structural formula (IV):

including salts, hydrates, solvates and N-oxides thereof, wherein R²,R⁵, R⁶ and L¹ are as previously defined for structural formula (I); LGis a leaving group, such as, for example, —S(O)₂Me, —SMe or halo (e.g.,F, Cl, Br, I) and.

In yet another embodiment, the intermediates are 4-amino- or4-hydroxy-2-pyrimidineamines according to structural formula (V):

including salts, hydrates, solvates and N-oxides thereof, wherein R²,R⁵, R⁶ and L¹ are as previously defined for structural formula (I), R⁷is an amino or hydroxyl group and R^(2c) is hydrogen or a progroup.

In another embodiment, the intermediates are N4-substituted cytosinesaccording to structural formula (VI):

including salts, hydrates, solvates and N-oxides thereof, wherein R⁴,R⁵, R⁶ and L² are as previously defined for structural formula (I) andR^(4c) is as previously defined in formula (III).

In yet another aspect, the present invention provides methods ofsynthesizing the 2,4-pyrimidinediamine compounds and prodrugs of theinvention. In one embodiment, the method involves reacting a4-pyrimidineamine according to structural formula (III) with an amine ofthe formula HR^(2c)N-L¹-R², where L¹, R² and R^(2c) are as previouslydefined for structural formula (IV) to yield a 2,4-pyrimidinediamineaccording to structural formula (I) or a prodrug according to structuralformula (II).

In another embodiment, the method involves reacting a 2-pyrimidineamineaccording to structural formula (IV) with an amine of the formulaR⁴-L²-NHR^(4c) where L⁴, R⁴ and R^(4c) are as previously defined forstructural formula (III) to yield a 2,4-pyrimidinediamine according tostructural formula (I) or a prodrug according to structural formula(II).

In yet another embodiment, the method involves reacting a4-amino-2-pyrimidineamine according to structural formula (V) (in whichR⁷ is an amino group) with an amine of the formula R⁴-L²-NHR^(4c), whereL², R⁴ and R^(4c) are as defined for structural formula (III), to yielda 2,4-pyrimidinediamine according to structural formula (I) or a prodrugaccording to structural formula (II). Alternatively, the4-amino-2-pyrimidineamine may be reacted with a compound of the formulaR⁴-L²-LG, where R⁴ and L² are as previously defined for structuralformula (I) and LG is a leaving group.

In still another embodiment, the method involves halogenating a4-hydroxy-2-pyrimidineamine according to structural formula (V) (R⁷ is ahydroxyl group) to yield a 2-pyrimidineamine according to structuralformula (IV) and reacting this pyrimidineamine with an appropriateamine, as described above.

In yet another embodiment, the method involves halogenating anN4-substituted cytosine according to structural formula (VI) to yield a4-pyrimidineamine according to structural formula (III) and reactingthis pyrimidineamine with an appropriate amine, as described above.

The 2,4-pyrimidinediamine compounds of the invention are potentinhibitors of degranulation of immune cells, such as mast, basophil,neutrophil and/or eosinophil cells. Thus, in still another aspect, thepresent invention provides methods of regulating, and in particularinhibiting, degranulation of such cells. The method generally involvescontacting a cell that degranulates with an amount of a2,4-pyrimidinediamine compound or prodrug of the invention, or anacceptable salt, hydrate, solvate, N-oxide and/or composition thereof,effective to regulate or inhibit degranulation of the cell. The methodmay be practiced in in vitro contexts or in in vivo contexts as atherapeutic approach towards the treatment or prevention of diseasescharacterized by, caused by or associated with cellular degranulation.

While not intending to be bound by any theory of operation, biochemicaldata confirm that the 2,4-pyrimidinediamine compounds exert theirdegranulation inhibitory effect, at least in part, by blocking orinhibiting the signal transduction cascade(s) initiated by crosslinkingof the high affinity Fc receptors for IgE (“FcεRI”) and/or IgG(“FcγRI”). Indeed, the 2,4-pyrimidinediamine compounds are potentinhibitors of both FcεRI-mediated and FcγRI-mediated degranulation. As aconsequence, the 2,4-pyrimidine compounds may be used to inhibit theseFc receptor signalling cascades in any cell type expressing such FcεRIand/or FcγRI receptors including but not limited to macrophages, mast,basophil, neutrophil and/or eosinophil cells.

The methods also permit the regulation of, and in particular theinhibition of, downstream processes that result as a consequence ofactivating such Fc receptor signaling cascade(s). Such downstreamprocesses include, but are not limited to, FcεRI-mediated and/orFcγRI-mediated degranulation, cytokine production and/or the productionand/or release of lipid mediators such as leukotrienes andprostaglandins. The method generally involves contacting a cellexpressing an Fc receptor, such as one of the cell types discussedabove, with an amount of a 2,4-pyrimidinediamine compound or prodrug ofthe invention, or an acceptable salt, hydrate, solvent, N-oxide and/orcomposition thereof, effective to regulate or inhibit the Fc receptorsignaling cascade and/or a downstream process effected by the activationof this signaling cascade. The method may be practiced in in vitrocontexts or in in vivo contexts as a therapeutic approach towards thetreatment or prevention of diseases characterized by, caused by orassociated with the Fc receptor signaling cascade, such as diseaseseffected by the release of granule specific chemical mediators upondegranulation, the release and/or synthesis of cytokines and/or therelease and/or synthesis of lipid mediators such as leukotrienes andprostaglandins.

In yet another aspect, the present invention provides methods oftreating and/or preventing diseases characterized by, caused by orassociated with the release of chemical mediators as a consequence ofactivating Fc receptor signaling cascades, such as FcεRI and/orFcγRI-signaling cascades. The methods may be practiced in animals inveterinary contexts or in humans. The methods generally involveadministering to an animal subject or human an amount of a2,4-pyrimidinediamine compound or prodrug of the invention, or anacceptable salt, hydrate, solvate, N-oxide and/or composition thereof,effective to treat or prevent the disease. As discussed previously,activation of the FcεRI or FcγRI receptor signaling cascade in certainimmune cells leads to the release and/or synthesis of a variety ofchemical substances that are pharmacological mediators of a wide varietyof diseases. Any of these diseases may be treated or prevented accordingto the methods of the invention.

For example, in mast cells and basophil cells, activation of the FcεRIor FcγRI signaling cascade leads to the immediate (i.e., within 1-3 min.of receptor activation) release of preformed mediators of atopic and/orType I hypersensitivity reactions (e.g., histamine, proteases such astryptase, etc.) via the degranulation process. Such atopic or Type Ihypersensitivity reactions include, but are not limited to, anaphylacticreactions to environmental and other allergens (e.g., pollens, insectand/or animal venoms, foods, drugs, contrast dyes, etc.), anaphylactoidreactions, hay fever, allergic conjunctivitis, allergic rhinitis,allergic asthma, atopic dermatitis, eczema, urticaria, mucosaldisorders, tissue disorders and certain gastrointestinal disorders.

The immediate release of the preformed mediators via degranulation isfollowed by the release and/or synthesis of a variety of other chemicalmediators, including, among other things, platelet activating factor(PAF), prostaglandins and leukotrienes (e.g., LTC4) and the de novosynthesis and release of cytokines such as TNFα, IL-4, IL-5, IL-6,IL-13, etc. The first of these two processes occurs approximately 3-30min. following receptor activation; the latter approximately 30 min.-7hrs. following receptor activation. These “late stage” mediators arethought to be in part responsible for the chronic symptoms of theabove-listed atopic and Type I hypersensitivity reactions, and inaddition are chemical mediators of inflammation and inflammatorydiseases (e.g., osteoarthritis, inflammatory bowel disease, ulcerativecolitis, Crohn's disease, idiopathic inflammatory bowel disease,irritable bowel syndrome, spastic colon, etc.), low grade scarring(e.g., scleroderma, increased fibrosis, keloids, post-surgical scars,pulmonary fibrosis, vascular spasms, migraine, reperfusion injury andpost myocardial infarction), and sicca complex or syndrome. All of thesediseases may be treated or prevented according to the methods of theinvention.

Additional diseases which can be treated or prevented according to themethods of the invention include diseases associated with basophil celland/or mast cell pathology. Examples of such diseases include, but arenot limited to, diseases of the skin such as scleroderma, cardiacdiseases such as post myocardial infarction, pulmonary diseases such aspulmonary muscle changes or remodeling and chronic obstructive pulmonarydisease (COPD) and diseases of the gut such as inflammatory bowelsyndrome (spastic colon).

The 2,4-pyrimidinediamine compounds of the invention are also potentinhibitors of the tyrosine kinase Syk kinase. Thus, in still anotheraspect, the present invention provides methods of regulating, and inparticular inhibiting, Syk kinase activity. The method generallyinvolves contacting a Syk kinase or a cell comprising a Syk kinase withan amount of a 2,4-pyrimidinediamine compound or prodrug of theinvention, or an acceptable salt, hydrate, solvate, N-oxide and/orcomposition thereof, effective to regulate or inhibit Syk kinaseactivity. In one embodiment, the Syk kinase is an isolated orrecombinant Syk kinase. In another embodiment, the Syk kinase is anendogenous or recombinant Syk kinase expressed by a cell, for example amast cell or a basophil cell. The method may be practiced in in vitrocontexts or in in vivo contexts as a therapeutic approach towards thetreatment or prevention of diseases characterized by, caused by orassociated with Syk kinase activity.

While not intending to be bound by any particular theory of operation,it is believed that the 2,4-pyrimdinediamine compounds of the inventioninhibit cellular degranulation and/or the release of other chemicalmediators primarily by inhibiting Syk kinase that gets activated throughthe gamma chain homodimer of FcεRI (see, e.g., FIG. 2). This gamma chainhomodimer is shared by other Fc receptors, including FcγRI, FcγRIII andFcαRI. For all of these receptors, intracellular signal transduction ismediated by the common gamma chain homodimer. Binding and aggregation ofthose receptors results in the recruitment and activation of tyrosinekinases such as Syk kinase. As a consequence of these common signalingactivities, the 2,4-pyrimidinediamine compounds described herein may beused to regulate, and in particular inhibit, the signaling cascades ofFc receptors having this gamma chain homodimer, such as FcεRI, FcγRI,FcγRIII and FcαRI, as well as the cellular responses elicited throughthese receptors.

Syk kinase is known to play a critical role in other signaling cascades.For example, Syk kinase is an effector of B-cell receptor (BCR)signaling (Turner et al., 2000, Immunology Today 21:148-154) and is anessential component of integrin beta(1), beta(2) and beta(3) signalingin neutrophils (Mocsai et al., 2002, Immunity 16:547-558). As the2,4-pyrimidinediamine compounds described herein are potent inhibitorsof Syk kinase, they can be used to regulate, and in particular inhibit,any signaling cascade where Syk plays a role, such as, fore example, theFc receptor, BCR and integrin signaling cascades, as well as thecellular responses elicited through these signaling cascades. Theparticular cellular response regulated or inhibited will depend, inpart, on the specific cell type and receptor signaling cascade, as iswell known in the art. Non-limiting examples of cellular responses thatmay be regulated or inhibited with the 2,4-pyrimidinediamine compoundsinclude a respiratory burst, cellular adhesion, cellular degranulation,cell spreading, cell migration, phagocytosis (e.g., in macrophages),calcium ion flux (e.g., in mast, basophil, neutrophil, eosinophil andB-cells), platelet aggregation, and cell maturation (e.g., in B-cells).

Thus, in another aspect, the present invention provides methods ofregulating, and in particular inhibiting, signal transduction cascadesin which Syk plays a role. The method generally involves contacting aSyk-dependent receptor or a cell expressing a Syk-dependent receptorwith an amount of a 2,4-pyrimidinediamine compound or prodrug of theinvention, or an acceptable salt, hydrate, solvate, N-oxide and/orcomposition thereof, effective to regulate or inhibit the signaltransduction cascade. The methods may also be used to regulate, and inparticular inhibit, downstream processes or cellular responses elicitedby activation of the particular Syk-dependent signal transductioncascade. The methods may be practiced to regulate any signaltransduction cascade where Syk is not known or later discovered to playa role. The methods may be practiced in in vitro contexts or in in vivocontexts as a therapeutic approach towards the treatment or preventionof diseases characterized by, caused by or associated with activation ofthe Syk-dependent signal transduction cascade. Non-limited examples ofsuch diseases include those previously discussed.

Cellular and animal data also confirm that the 2,4-pyrimidinediaminecompounds of the invention may also be used to treat or preventautoimmune diseases and/or symptoms of such diseases. The methodsgenerally involve administering to a subject suffering from anautoimmune disease or at risk of developing an autoimmune disease anamount of a 2,4-pyrimidinediamine method or prodrug of the invention, oran acceptable salt, N-oxide, hydrate, solvate or composition thereof,effective to treat or prevent the autoimmune disease and/or itsassociated symptoms. Autoimmune diseases that can be treated orprevented with the 2,4-pyrimidinediamine compounds include thosediseases that are commonly associated with nonanaphylactichypersensitivity reactions (Type II, Type III and/or Type IVhypersensitivity reactions) and/or those diseases that are mediated, atleast in part, by activation of the FcγR signaling cascade in monocytecells. Such autoimmune disease include, but are not limited to, thoseautoimmune diseases that are frequently designated as single organ orsingle cell-type autoimmune disorders and those autoimmune disease thatare frequently designated as involving systemic autoimmune disorder.Non-limiting examples of diseases frequently designated as single organor single cell-type autoimmune disorders include: Hashimoto'sthyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritisof pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis,Goodpasture's disease, autoimmune thrombocytopenia, sympatheticophthalmia, myasthenia gravis, Graves' disease, primary biliarycirrhosis, chronic aggressive hepatitis, ulcerative colitis andmembranous glomerulopathy. Non-limiting examples of diseases oftendesignated as involving systemic autoimmune disorder include: systemiclupus erythematosis, rheumatoid arthritis, Sjogren's syndrome, Reiter'ssyndrome, polymyositis-dermatomyositis, systemic sclerosis,polyarteritis nodosa, multiple sclerosis and bullous pemphigoid.

5. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 provides a cartoon illustrating allergen-induced production ofIgE and consequent release of preformed and other chemical mediatorsfrom mast cells;

FIG. 2 provides a cartoon illustrating the FcεRI signal transductioncascade leading to degranulation of mast and/or basophil cells; and

FIG. 3 provides a cartoon illustrating the putative points of action ofcompounds that selectively inhibit upstream FcεRI-mediated degranulationand compounds that inhibit both FcεRI-mediated and ionomycin-induceddegranulation.

6. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 6.1 Definitions

As used herein, the following terms are intended to have the followingmeanings:

“Alkyl” by itself or as part of another substituent refers to asaturated or unsaturated branched, straight-chain or cyclic monovalenthydrocarbon radical having the stated number of carbon atoms (i.e.,C1-C6 means one to six carbon atoms) that is derived by the removal ofone hydrogen atom from a single carbon atom of a parent alkane, alkeneor alkyne. Typical alkyl groups include, but are not limited to, methyl;ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl,propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl,prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl,butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. Wherespecific levels of saturation are intended, the nomenclature “alkanyl,”“alkenyl” and/or “alkynyl” is used, as defined below. In preferredembodiments, the alkyl groups are (C1-C6) alkyl.

“Alkanyl” by itself or as part of another substituent refers to asaturated branched, straight-chain or cyclic alkyl derived by theremoval of one hydrogen atom from a single carbon atom of a parentalkane. Typical alkanyl groups include, but are not limited to,methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl(isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl,butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl),2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like. Inpreferred embodiments, the alkanyl groups are (C1-C6) alkanyl.

“Alkenyl” by itself or as part of another substituent refers to anunsaturated branched, straight-chain or cyclic alkyl having at least onecarbon-carbon double bond derived by the removal of one hydrogen atomfrom a single carbon atom of a parent alkene. The group may be in eitherthe cis or trans conformation about the double bond(s). Typical alkenylgroups include, but are not limited to, ethenyl; propenyls such asprop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl,cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such asbut-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.;and the like. In preferred embodiments, the alkenyl group is (C2-C6)alkenyl.

“Alkynyl” by itself or as part of another substituent refers to anunsaturated branched, straight-chain or cyclic alkyl having at least onecarbon-carbon triple bond derived by the removal of one hydrogen atomfrom a single carbon atom of a parent alkyne. Typical alkynyl groupsinclude, but are not limited to, ethynyl; propynyls such asprop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl,but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. In preferredembodiments, the alkynyl group is (C2-C6) alkynyl.

“Alkyldiyl” by itself or as part of another substituent refers to asaturated or unsaturated, branched, straight-chain or cyclic divalenthydrocarbon group having the stated number of carbon atoms (i.e., C1-C6means from one to six carbon atoms) derived by the removal of onehydrogen atom from each of two different carbon atoms of a parentalkane, alkene or alkyne, or by the removal of two hydrogen atoms from asingle carbon atom of a parent alkane, alkene or alkyne. The twomonovalent radical centers or each valency of the divalent radicalcenter can form bonds with the same or different atoms. Typicalalkyldiyl groups include, but are not limited to, methandiyl; ethyldiylssuch as ethan-1,1-diyl, ethan-1,2-diyl, ethen-1,1-diyl, ethen-1,2-diyl;propyldiyls such as propan-1,1-diyl, propan-1,2-diyl, propan-2,2-diyl,propan-1,3-diyl, cyclopropan-1,1-diyl, cyclopropan-1,2-diyl,prop-1-en-1,1-diyl, prop-1-en-1,2-diyl, prop-2-en-1,2-diyl,prop-1-en-1,3-diyl, cycloprop-1-en-1,2-diyl, cycloprop-2-en-1,2-diyl,cycloprop-2-en-1,1-diyl, prop-1-yn-1,3-diyl, etc.; butyldiyls such as,butan-1,1-diyl, butan-1,2-diyl, butan-1,3-diyl, butan-1,4-diyl,butan-2,2-diyl, 2-methyl-propan-1,1-diyl, 2-methyl-propan-1,2-diyl,cyclobutan-1,1-diyl; cyclobutan-1,2-diyl, cyclobutan-1,3-diyl,but-1-en-1,1-diyl, but-1-en-1,2-diyl, but-1-en-1,3-diyl,but-1-en-1,4-diyl, 2-methyl-prop-1-en-1,1-diyl,2-methanylidene-propan-1,1-diyl, buta-1,3-dien-1,1-diyl,buta-1,3-dien-1,2-diyl, buta-1,3-dien-1,3-diyl, buta-1,3-dien-1,4-diyl,cyclobut-1-en-1,2-diyl, cyclobut-1-en-1,3-diyl, cyclobut-2-en-1,2-diyl,cyclobuta-1,3-dien-1,2-diyl, cyclobuta-1,3-dien-1,3-diyl,but-1-yn-1,3-diyl, but-1-yn-1,4-diyl, buta-1,3-diyn-1,4-diyl, etc.; andthe like. Where specific levels of saturation are intended, thenomenclature alkanyldiyl, alkenyldiyl and/or alkynyldiyl is used. Whereit is specifically intended that the two valencies are on the samecarbon atom, the nomenclature “alkylidene” is used. In preferredembodiments, the alkyldiyl group is (C1-C6) alkyldiyl. Also preferredare saturated acyclic alkanyldiyl groups in which the radical centersare at the terminal carbons, e.g., methandiyl (methano);ethan-1,2-diyl(ethano); propan-1,3-diyl(propano);butan-1,4-diyl(butano); and the like (also referred to as alkylenos,defined infra).

“Alkyleno” by itself or as part of another substituent refers to astraight-chain saturated or unsaturated alkyldiyl group having twoterminal monovalent radical centers derived by the removal of onehydrogen atom from each of the two terminal carbon atoms ofstraight-chain parent alkane, alkene or alkyne. The locant of a doublebond or triple bond, if present, in a particular alkyleno is indicatedin square brackets. Typical alkyleno groups include, but are not limitedto, methano; ethylenos such as ethano, etheno, ethyno; propylenos suchas propano, prop[1]eno, propa[1,2]dieno, prop[1]yno, etc.; butylenossuch as butano, but[1]eno, but[2]eno, buta[1,3]dieno, but[1]yno,but[2]yno, buta[1,3]diyno, etc.; and the like. Where specific levels ofsaturation are intended, the nomenclature alkano, alkeno and/or alkynois used. In preferred embodiments, the alkyleno group is (C1-C6) or(C1-C3) alkyleno. Also preferred are straight-chain saturated alkanogroups, e.g., methano, ethano, propano, butano, and the like.

“Heteroalkyl,” Heteroalkanyl,” Heteroalkenyl,” Heteroalkynyl,”Heteroalkyldiyl” and “Heteroalkyleno” by themselves or as part ofanother substituent refer to alkyl, alkanyl, alkenyl, alkynyl, alkyldiyland alkyleno groups, respectively, in which one or more of the carbonatoms are each independently replaced with the same or differentheteroatoms or heteroatomic groups. Typical heteroatoms and/orheteroatomic groups which can replace the carbon atoms include, but arenot limited to, —O—, —S—, —S—O—, —NR′—, —PH—, —S(O)—, —S(O)₂—,—S(O)NR′—, —S(O)₂NR′—, and the like, including combinations thereof,where each R′ is independently hydrogen or (C1-C6) alkyl.

“Cycloalkyl” and “Heterocycloalkyl” by themselves or as part of anothersubstituent refer to cyclic versions of “alkyl” and “heteroalkyl”groups, respectively. For heteroalkyl groups, a heteroatom can occupythe position that is attached to the remainder of the molecule. Typicalcycloalkyl groups include, but are not limited to, cyclopropyl;cyclobutyls such as cyclobutanyl and cyclobutenyl; cyclopentyls such ascyclopentanyl and cyclopentenyl; cyclohexyls such as cyclohexanyl andcyclohexenyl; and the like. Typical heterocycloalkyl groups include, butare not limited to, tetrahydrofuranyl (e.g., tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, etc.), piperidinyl (e.g., piperidin-1-yl,piperidin-2-yl, etc.), morpholinyl (e.g., morpholin-3-yl,morpholin-4-yl, etc.), piperazinyl (e.g., piperazin-1-yl,piperazin-2-yl, etc.), and the like.

“Acyclic Heteroatomic Bridge” refers to a divalent bridge in which thebackbone atoms are exclusively heteroatoms and/or heteroatomic groups.Typical acyclic heteroatomic bridges include, but are not limited to,—O—, —S—, —S—O—, —NR′—, —PH—, —S(O)—, —S(O)₂—, —S(O) NR′—, —S(O)₂NR′—,and the like, including combinations thereof, where each R′ isindependently hydrogen or (C1-C6) alkyl.

“Parent Aromatic Ring System” refers to an unsaturated cyclic orpolycyclic ring system having a conjugated π electron system.Specifically included within the definition of “parent aromatic ringsystem” are fused ring systems in which one or more of the rings arearomatic and one or more of the rings are saturated or unsaturated, suchas, for example, fluorene, indane, indene, phenalene,tetrahydronaphthalene, etc. Typical parent aromatic ring systemsinclude, but are not limited to, aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, tetrahydronaphthalene, triphenylene, trinaphthalene, and thelike, as well as the various hydro isomers thereof.

“Aryl” by itself or as part of another substituent refers to amonovalent aromatic hydrocarbon group having the stated number of carbonatoms (i.e., C5-C15 means from 5 to 15 carbon atoms) derived by theremoval of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Typical aryl groups include, but are not limitedto, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene, and the like, as well as thevarious hydro isomers thereof. In preferred embodiments, the aryl groupis (C5-C15) aryl, with (C5-C10) being even more preferred. Particularlypreferred aryls are cyclopentadienyl, phenyl and naphthyl.

“Arylaryl” by itself or as part of another substituent refers to amonovalent hydrocarbon group derived by the removal of one hydrogen atomfrom a single carbon atom of a ring system in which two or moreidentical or non-identical parent aromatic ring systems are joineddirectly together by a single bond, where the number of such direct ringjunctions is one less than the number of parent aromatic ring systemsinvolved. Typical arylaryl groups include, but are not limited to,biphenyl, triphenyl, phenyl-naphthyl, binaphthyl, biphenyl-naphthyl, andthe like. Where the number of carbon atoms in an arylaryl group arespecified, the numbers refer to the carbon atoms comprising each parentaromatic ring. For example, (C5-C15) arylaryl is an arylaryl group inwhich each aromatic ring comprises from 5 to 15 carbons, e.g., biphenyl,triphenyl, binaphthyl, phenylnaphthyl, etc. Preferably, each parentaromatic ring system of an arylaryl group is independently a (C5-C15)aromatic, more preferably a (C5-C10) aromatic. Also preferred arearylaryl groups in which all of the parent aromatic ring systems areidentical, e.g., biphenyl, triphenyl, binaphthyl, trinaphthyl, etc.

“Biaryl” by itself or as part of another substituent refers to anarylaryl group having two identical parent aromatic systems joineddirectly together by a single bond. Typical biaryl groups include, butare not limited to, biphenyl, binaphthyl, bianthracyl, and the like.Preferably, the aromatic ring systems are (C5-C15) aromatic rings, morepreferably (C5-C10) aromatic rings. A particularly preferred biarylgroup is biphenyl.

“Arylalkyl” by itself or as part of another substituent refers to anacyclic alkyl group in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced withan aryl group. Typical arylalkyl groups include, but are not limited to,benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl,2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl and the like. Where specific alkyl moietiesare intended, the nomenclature arylalkanyl, arylakenyl and/orarylalkynyl is used. In preferred embodiments, the arylalkyl group is(C6-C21) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of thearylalkyl group is (C1-C6) and the aryl moiety is (C5-C15). Inparticularly preferred embodiments the arylalkyl group is (C6-C13),e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is(C1-C3) and the aryl moiety is (C5-C10).

“Parent Heteroaromatic Ring System” refers to a parent aromatic ringsystem in which one or more carbon atoms are each independently replacedwith the same or different heteroatoms or heteroatomic groups. Typicalheteroatoms or heteroatomic groups to replace the carbon atoms include,but are not limited to, N, NH, P, O, S, S(O), S(O)₂, Si, etc.Specifically included within the definition of “parent heteroaromaticring systems” are fused ring systems in which one or more of the ringsare aromatic and one or more of the rings are saturated or unsaturated,such as, for example, benzodioxan, benzofuran, chromane, chromene,indole, indoline, xanthene, etc. Also included in the definition of“parent heteroaromatic ring system” are those recognized rings thatinclude common substituents, such as, for example, benzopyrone and1-methyl-1,2,3,4-tetrazole. Specifically excluded from the definition of“parent heteroaromatic ring system” are benzene rings fused to cyclicpolyalkylene glycols such as cyclic polyethylene glycols. Typical parentheteroaromatic ring systems include, but are not limited to, acridine,benzimidazole, benzisoxazole, benzodioxan, benzodioxole, benzofuran,benzopyrone, benzothiadiazole, benzothiazole, benzotriazole,benzoxaxine, benzoxazole, benzoxazoline, carbazole, β-carboline,chromane, chromene, cinnoline, furan, imidazole, indazole, indole,indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazole, xanthene, and the like.

“Heteroaryl” by itself or as part of another substituent refers to amonovalent heteroaromatic group having the stated number of ring atoms(e.g., “5-14 membered” means from 5 to 14 ring atoms) derived by theremoval of one hydrogen atom from a single atom of a parentheteroaromatic ring system. Typical heteroaryl groups include, but arenot limited to, groups derived from acridine, benzimidazole,benzisoxazole, benzodioxan, benzodiaxole, benzofuran, benzopyrone,benzothiadiazole, benzothiazole, benzotriazole, benzoxazine,benzoxazole, benzoxazoline, carbazole, β-carboline, chromane, chromene,cinnoline, furan, imidazole, indazole, indole, indoline, indolizine,isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thelike, as well as the various hydro isomers thereof. In preferredembodiments, the heteroaryl group is a 5-14 membered heteroaryl, with5-10 membered heteroaryl being particularly preferred.

“Heteroaryl-Heteroaryl” by itself or as part of another substituentrefers to a monovalent heteroaromatic group derived by the removal ofone hydrogen atom from a single atom of a ring system in which two ormore identical or non-identical parent heteroaromatic ring systems arejoined directly together by a single bond, where the number of suchdirect ring junctions is one less than the number of parentheteroaromatic ring systems involved. Typical heteroaryl-heteroarylgroups include, but are not limited to, bipyridyl, tripyridyl,pyridylpurinyl, bipurinyl, etc. Where the number of atoms are specified,the numbers refer to the number of atoms comprising each parentheteroaromatic ring systems. For example, 5-15 memberedheteroaryl-heteroaryl is a heteroaryl-heteroaryl group in which eachparent heteroaromatic ring system comprises from 5 to 15 atoms, e.g.,bipyridyl, tripuridyl, etc. Preferably, each parent heteroaromatic ringsystem is independently a 5-15 membered heteroaromatic, more preferablya 5-10 membered heteroaromatic. Also preferred are heteroaryl-heteroarylgroups in which all of the parent heteroaromatic ring systems areidentical.

“Biheteroaryl” by itself or as part of another substituent refers to aheteroaryl-heteroaryl group having two identical parent heteroaromaticring systems joined directly together by a single bond. Typicalbiheteroaryl groups include, but are not limited to, bipyridyl,bipurinyl, biquinolinyl, and the like. Preferably, the heteroaromaticring systems are 5-15 membered heteroaromatic rings, more preferably5-10 membered heteroaromatic rings.

“Heteroarylalkyl” by itself or as part of another substituent refers toan acyclic alkyl group in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced with aheteroaryl group. Where specific alkyl moieties are intended, thenomenclature heteroarylalkanyl, heteroarylakenyl and/orheteroarylalkynyl is used. In preferred embodiments, the heteroarylalkylgroup is a 6-21 membered heteroarylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the heteroarylalkyl is (C1-C6) alkyl and theheteroaryl moiety is a 5-15-membered heteroaryl. In particularlypreferred embodiments, the heteroarylalkyl is a 6-13 memberedheteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety is (C1-C3)alkyl and the heteroaryl moiety is a 5-10 membered heteroaryl.

“Halogen” or “Halo” by themselves or as part of another substituent,unless otherwise stated, refer to fluoro, chloro, bromo and iodo.

“Haloalkyl” by itself or as part of another substituent refers to analkyl group in which one or more of the hydrogen atoms is replaced witha halogen. Thus, the term “haloalkyl” is meant to includemonohaloalkyls, dihaloalkyls, trihaloalkyls, etc. up to perhaloalkyls.For example, the expression “(C1-C2) haloalkyl” includes fluoromethyl,difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl,1,2-difluoroethyl, 1,1,1-trifluoroethyl, perfluoroethyl, etc.

The above-defined groups may include prefixes and/or suffixes that arecommonly used in the art to create additional well-recognizedsubstituent groups. As examples, “alkyloxy” or “alkoxy” refers to agroup of the formula —OR″, “alkylamine” refers to a group of the formula—NHR″ and “dialkylamine” refers to a group of the formula —NR″R″, whereeach R″ is independently an alkyl. As another example, “haloalkoxy” or“haloalkyloxy” refers to a group of the formula —OR′″, where R′″ is ahaloalkyl.

“Protecting group” refers to a group of atoms that, when attached to areactive functional group in a molecule, mask, reduce or prevent thereactivity of the functional group. Typically, a protecting group may beselectively removed as desired during the course of a synthesis.Examples of protecting groups can be found in Greene and Wuts,Protective Groups in Organic Chemistry, 3^(rd) Ed., 1999, John Wiley &Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods,Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative aminoprotecting groups include, but are not limited to, formyl, acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl(“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl(“TES”), trityl and substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl(“NVOC”) and the like. Representative hydroxyl protecting groupsinclude, but are not limited to, those where the hydroxyl group iseither acylated or alkylated such as benzyl and trityl ethers, as wellas alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g.,TMS or TIPPS groups) and allyl ethers.

“Prodrug” refers to a derivative of an active 2,4-pyrimidinediaminecompound (drug) that requires a transformation under the conditions ofuse, such as within the body, to release the active2,4-pyrimidinediamine drug. Prodrugs are frequently, but notnecessarily, pharmacologically inactive until converted into the activedrug. Prodrugs are typically obtained by masking a functional group inthe 2,4-pyrimidinediamine drug believed to be in part required foractivity with a progroup (defined below) to form a promoiety whichundergoes a transformation, such as cleavage, under the specifiedconditions of use to release the functional group, and hence the active2,4-pyrimidinediamine drug. The cleavage of the promoiety may proceedspontaneously, such as by way of a hydrolysis reaction, or it may becatalyzed or induced by another agent, such as by an enzyme, by light,by acid or base, or by a change of or exposure to a physical orenvironmental parameter, such as a change of temperature. The agent maybe endogenous to the conditions of use, such as an enzyme present in thecells to which the prodrug is administered or the acidic conditions ofthe stomach, or it may be supplied exogenously.

A wide variety of progroups, as well as the resultant promoieties,suitable for masking functional groups in the active2,4-pyrimidinediamines compounds to yield prodrugs are well-known in theart. For example, a hydroxyl functional group may be masked as asulfonate, ester or carbonate promoiety, which may be hydrolyzed in vivoto provide the hydroxyl group. An amino functional group may be maskedas an amide, carbamate, imine, urea, phosphenyl, phosphoryl or sulfenylpromoiety, which may be hydrolyzed in vivo to provide the amino group. Acarboxyl group may be masked as an ester (including silyl esters andthioesters), amide or hydrazide promoiety, which may be hydrolyzed invivo to provide the carboxyl group. Nitrogen protecting groups andnitrogen pro-drugs of the invention may include lower alkyl groups aswell as amides, carbamates, etc. Other specific examples of suitableprogroups and their respective promoieties will be apparent to those ofskill in the art.

“Progroup” refers to a type of protecting group that, when used to maska functional group within an active 2,4-pyrimidinediamine drug to form apromoiety, converts the drug into a prodrug. Progroups are typicallyattached to the functional group of the drug via bonds that arecleavable under specified conditions of use. Thus, a progroup is thatportion of a promoiety that cleaves to release the functional groupunder the specified conditions of use. As a specific example, an amidepromoiety of the formula —NH—C(O)CH₃ comprises the progroup —C(O)CH₃.

“Fc Receptor” refers to a member of the family of cell surface moleculesthat binds the Fc portion (containing the specific constant region) ofan immunoglobulin. Each Fc receptor binds immunoglobulins of a specifictype. For example the Fcα receptor (“FcαR”) binds IgA, the FcεR bindsIgE and the FcγR binds IgG.

The FcαR family includes the polymeric Ig receptor involved inepithelial transport of IgA/IgM, the myeloid specific receptor RcαRI(also called CD89), the Fcα/μR and at least two alternative IgAreceptors (for a recent review see Monteiro & van de Winkel, 2003, Annu.Rev. Immunol, advanced e-publication. The FcαRI is expressed onneutrophils, eosinophils, moncytes/macrophages, dendritic cells andkupfer cells. The FcαRI includes one alpha chain and the FcR gammahomodimer that bears an activation motif (ITAM) in the cytoplasmicdomain and phosphorylates Syk kinase.

The FcεR family includes two types, designated FcεRI and FcεRII (alsoknown as CD23). FcεRI is a high affinity receptor (binds IgE with anaffinity of about 10¹⁰M⁻¹) found on mast, basophil and eosinophil cellsthat anchors monomeric IgE to the cell surface. The FcεRI possesses onealpha chain, one beta chain and the gamma chain homodimer discussedabove. The FcεRII is a low affinity receptor expressed on mononuclearphagocytes, B lymphocytes, eosinophils and platelets. The FcεRIIcomprises a single polypeptide chain and does not include the gammachain homodimer.

The FcγR family includes three types, designated FcγRI (also known asCD64), FcγRII (also known as CD32) and FcγRIII (also known as CD16).FcγRI is a high affinity receptor (binds IgG1 with an affinity of10⁸M⁻¹) found on mast, basophil, mononuclear, neutrophil, eosinophil,deudritic and phagocyte cells that anchors nomomeric IgG to the cellsurface. The FcγRI includes one alpha chain and the gamma chain dimershared by FcαRI and FcεRI.

The FcγRII is a low affinity receptor expressed on neutrophils,monocytes, eosinophils, platelets and B lymphocytes. The FcγRII includesone alpha chain, and does not include the gamma chain homodimerdiscussed above.

The FcγRIII is a low affinity (bindes IgG1 with an affinity of 5×10⁵M⁻¹)expressed on NK, eosinophil, macrophage, neutrophil and mast cells. Itcomprises one alpha chain and the gamma homodimer shared by FcαRI, FcεRIand FcγRI.

Skilled artisans will recognize that the subunit structure and bindingproperties of these various Fc receptors, cell types expressing them,are not completely characterized. The above discussion merely reflectsthe current state-of-the-art regarding these receptors (see, e.g.,Immunobiology: The Immune System in Health & Disease, 5^(th) Edition,Janeway et al., Eds, 2001, ISBN 0-8153-3642-x, FIG. 9.30 at pp. 371),and is not intended to be limiting with respect to the myriad receptorsignaling cascades that can be regulated with the compounds describedherein.

“Fc Receptor-Mediated Degranulation” or “Fc Receptor-InducedDegranulation” refers to degranulation that proceeds via an Fc receptorsignal transduction cascade initiated by crosslinking of an Fc receptor.

“IgE-Induced Degranulation” or “FcεRI-Mediated Degranulation” refers todegranulation that proceeds via the IgE receptor signal transductioncascade initiated by crosslinking of FcεR1-bound IgE. The crosslinkingmay be induced by an IgE-specific allergen or other multivalent bindingagent, such as an anti-IgE antibody. Referring to FIG. 2, in mast and/orbasophil cells, the FcεRI signaling cascade leading to degranulation maybe broken into two stages: upstream and downstream. The upstream stageincludes all of the processes that occur prior to calcium ionmobilization (illustrated as “Ca²⁺” in FIG. 2; see also FIG. 3). Thedownstream stage includes calcium ion mobilization and all processesdownstream thereof. Compounds that inhibit FcεRI-mediated degranulationmay act at any point along the FcεRI-mediated signal transductioncascade. Compounds that selectively inhibit upstream FcεRI-mediateddegranulation act to inhibit that portion of the FcεRI signaling cascadeupstream of the point at which calcium ion mobilization is induced. Incell-based assays, compounds that selectively inhibit upstreamFcεRI-mediated degranulation inhibit degranulation of cells such as mastor basophil cells that are activated or stimulated with an IgE-specificallergen or binding agent (such as an anti-IgE antibody) but do notappreciably inhibit degranulation of cells that are activated orstimulated with degranulating agents that bypass the FcεRI signalingpathway, such as, for example the calcium ionophores ionomycin andA23187.

“IgG-Induced Degranulation” or “FcγRI-Mediated Degranulation” refers todegranulation that proceeds via the FcγRI signal transduction cascadeinitiated by crosslinking of FcγRI-bound IgG. The crosslinking may beinduced by an IgG-specific allergen or another multivalent bindingagent, such as an anti-IgG or fragment antibody. Like the FcεRIsignaling cascade, in mast and basophil cells the FcγRI signalingcascade also leads to degranulation which may be broken into the sametwo stages: upstream and downstream. Similar to FcεRI-mediateddegranulation, compounds that selectively inhibit upstreamFcγRI-mediated degranulation act upstream of the point at which calciumion mobilization is induced. In cell-based assays, compounds thatselectively inhibit upstream FcγRI-mediated degranulation inhibitdegranulation of cells such as mast or basophil cells that are activatedor stimulated with an IgG-specific allergen or binding agent (such as ananti-IgG antibody or fragment) but do not appreciably inhibitdegranulation of cells that are activated or stimulated withdegranulating agents that bypass the FcγRI signaling pathway, such as,for example the calcium ionophores ionomycin and A23187.

“Ionophore-Induced Degranulation” or “Ionophore-Mediated Degranulation”refers to degranulation of a cell, such as a mast or basophil cell, thatoccurs upon exposure to a calcium ionophore such as, for example,ionomycin or A23187.

“Syk Kinsase” refers to the well-known 72 kDa non-receptor (cytoplasmic)spleen protein tyrosine kinase expressed in B-cells and otherhematopoetic cells. Syk kinase includes two consensus Src-homology 2(SH2) domains in tandem that bind to phosphorylated immunoreceptortyrosine-based activation motifs (“ITAMs”), a “linker” domain and acatalytic domain (for a review of the structure and function of Sykkinase see Sada et al., 2001, J. Biochem. (Tokyo) 130:177-186); see alsoTurner et al., 2000, Immunology Today 21:148-154). Syk kinase has beenextensively studied as an effector of B-cell receptor (BCR) signaling(Turner et al., 2000, supra). Syk kinase is also critical for tyrosinephosphorylation of multiple proteins which regulate important pathwaysleading from immunoreceptors, such as Ca²⁺ mobilization andmitogen-activated protein kinase (MAPK) cascades (see, e.g., FIG. 2) anddegranulation. Syk kinase also plays a critical role in integrinsignaling in neutrophils (see, e.g., Mocsai et al. 2002, Immunity16:547-558).

As used herein, Syk kinase includes kinases from any species of animal,including but not limited to, homosapiens, simian, bovine, porcine,rodent, etc., recognized as belonging to the Syk family. Specificallyincluded are isoforms, splice variants, allelic variants, mutants, bothnaturally occurring and man-made. The amino acid sequences of such Sykkinases are well known and available from GENBANK. Specific examples ofmRNAs encoding different isoforms of human Syk kinase can be found atGENBANK accession no. gi|21361552|ref|0003177.2|,gi|1496899|emb|Z29630.1|HSSYKPTK[496899] andgi|15030258|gb|BC011399.1|BC011399[15030258], which are incorporatedherein by reference.

Skilled artisans will appreciate that tyrosine kinases belonging toother families may have active sites or binding pockets that are similarin three-dimensional structure to that of Syk. As a consequence of thisstructural similarity, such kinases, referred to herein as “Syk mimics,”are expected to catalyze phosphorylation of substrates phosphorylated bySyk. Thus, it will be appreciated that such Syk mimics, signaltransduction cascades in which such Syk mimics play a role andbiological responses effected by such Syk mimics and Syk mimic-dependentsignaling cascades may be regulated, and in particular inhibited, withthe 2,4-pyrimidinediamine compounds described herein. “Syk-DependentSignaling Cascade” refers to a signal transduction cascade in which

Syk kinase plays a role. Non-limiting examples of such Syk-dependentsignaling cascades include the FcαRI, FcεRI, FcγRI, FcγRIII, BCR andintegrin signaling cascades.

“Autoimmune Disease” refers to those diseases which are commonlyassociated with the nonanaphylactic hypersensitivity reactions (Type II,Type III and/or Type IV hypersensitivity reactions) that generallyresult as a consequence of the subject's own humoral and/orcell-mediated immune response to one or more immunogenic substances ofendogenous and/or exogenous origin. Such autoimmune diseases aredistinguished from diseases associated with the anaphylactic (Type I orIgE-mediated) hypersensitivity reactions.

6.2 the 2,4-Pyrimidinediamine Compounds

The compounds of the invention are generally 2,4-pyrimidinediaminecompounds according to structural formula (I):

including salts, hydrates, solvates and N-oxides thereof, wherein:

L¹ and L² are each, independently of one another, selected from thegroup consisting of a direct bond and a linker;

R² and R⁴ are as described in the following embodiments and examples;

R⁵ is selected from the group consisting of R⁶, (C1-C6) alkyl optionallysubstituted with one or more of the same or different R⁸ groups, (C1-C4)alkanyl optionally substituted with one or more of the same or differentR⁸ groups, (C2-C4) alkenyl optionally substituted with one or more ofthe same or different R⁸ groups and (C2-C4) alkynyl optionallysubstituted with one or more of the same or different R⁸ groups;

-   -   each R⁶ independently is selected from the group consisting of        hydrogen, an electronegative group, —OR^(d), —SR^(d), (C1-C3)        haloalkyloxy, (C1-C3) perhaloalkyloxy, —NR^(c)R^(c), halogen,        (C1-C3) haloalkyl,(C1-C3) perhaloalkyl, —CF₃, —CH₂CF₃, —CF₂CF₃,        —CN, —NC, —OCN, —SCN, —NO, —NO₂, —N₃, —S(O)R^(d), —S(O)₂R^(d),        —S(O)₂OR^(d), —S(O)NR^(c)R^(c), —S(O)₂NR^(c)R^(c), —OS(O)R^(d),        —OS(O)₂R^(d), —OS(O)₂OR^(d), —OS(O)NR^(c)R^(c),        —OS(O)₂NR^(c)R^(c), —C(O)R^(d), —C(O)OR^(d), —C(O)NR^(c)R^(c),        —C(NH)NR^(c)R^(c), —OC(O)R^(d), —SC(O)R^(d), —OC(O)OR^(d),        —SC(O)OR^(d), —OC(O)NR^(c)R^(c), —SC(O)NR^(c)R^(c),        —OC(NH)NR^(c)R^(c), —SC(NH)NR^(c)R^(c), —[NHC(O)]_(n)R^(d),        —[NHC(O)]_(n)OR^(d), —[NHC(O)]_(n)NR^(c)R^(c) and        —[NHC(NH)]_(n)NR^(c)R^(c), (C5-C10) aryl optionally substituted        with one or more of the same or different R⁸ groups, phenyl        optionally substituted with one or more of the same or different        R⁸ groups, (C6-C16) arylalkyl optionally substituted with one or        more of the same or different R⁸ groups, 5-10 membered        heteroaryl optionally substituted with one or more of the same        or different R⁸ groups and 6-16 membered heteroarylalkyl        optionally substituted with one or more of the same or different        R⁸ groups;

R⁸ is selected from the group consisting of R^(a), R^(b), R^(a)substituted with one or more of the same or different R^(a) or R^(b),—OR^(a) substituted with one or more of the same or different R^(a) orR^(b), —B(OR^(a))₂, —B(NR^(c)R^(c))₂, —(CH₂)_(m)—R^(b),—(CHR^(a))_(m)—R^(b), —O—(CH₂)_(m)—R^(b), —S—(CH₂)_(m)—R^(b),—O—CHR^(a)R^(b), —O—CR^(a)(R^(b))₂, —O—(CHR^(a))_(m)—R^(b),—O—(CH₂)_(m)CH[(CH₂)_(m)R^(b)]R^(b), —S—(CHR^(a))_(m)—R^(b),—C(O)NH—(CH₂)_(m)R^(b), —C(O)NH—(CHR^(a))_(m)—R^(b),—O—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b),—S—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b),—O—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b),—S—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b), —NH—(CH₂)_(m)—R^(b),—NH—(CHR^(a))_(m)R^(b), —NH[(CH₂)_(m)R^(b)], —N[(CH₂)_(m)R^(b)]₂,—NH—C(O)—NH—(CH₂)_(m)—R^(b), —NH—C(O)—(CH₂)^(m)—CHR^(b)R^(b) and—NH—(CH₂)_(m)—C(O)—NH—(CH₂)_(m)—R^(b);

each R^(a) is independently selected from the group consisting ofhydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11)cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl,piperazinyl, homopiperazinyl, piperidinyl, 4-11 memberedcycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 memberedheteroarylalkyl;

each R^(b) is a suitable group independently selected from the groupconsisting of ═O, —OR^(d), (C1-C3) haloalkyloxy, —OCF₃, ═S, —SR^(d),═NR^(d), ═NOR^(d), —NR^(c)R^(c), halogen, —CF₃, —CN, —NC, —OCN, —SCN,—NO, —NO₂, ═N₂, —N₃, —S(O)R^(d), —S(O)₂R^(d), —S(O)₂OR^(d),—S(O)NR^(c)R^(c), —S(O)₂NR^(c)R^(c), —OS(O)R^(d), —OS(O)₂R^(d),—OS(O)₂OR^(d), —OS(O)₂NR^(c)R^(c), —C(O)R^(d), —C(O)OR^(d),—C(O)NR^(c)R^(c), —C(NH)NR^(c)R^(c), —C(NR^(a))NR^(c)R^(c),—C(NOH)R^(a), —C(NOH)NR^(c)R^(c), —OC(O)R^(d), —OC(O)OR^(d),—OC(O)NR^(c)R^(c), —OC(NH)NR^(c)R^(c), —OC(NR^(a))NR^(c)R^(c),—[NHC(O)]_(n)R^(d), —[NR^(a)C(O)]_(n)R^(d), —[NHC(O)]_(n)OR^(d),—[NR^(a)C(O)]_(n)OR^(d), —[NHC(O)]_(n)NR^(c)R^(c),—[NR^(a)C(O)]_(n)NR^(c)R^(c), —[NHC(NH)]_(n)NR^(c)R^(c) and—[NR^(a)C(NR^(a))]_(n)NR^(c)R^(c);

each R^(c) is independently R^(a), or, alternatively, each R^(c) istaken together with the nitrogen atom to which it is bonded to form a 5to 8-membered cycloheteroalkyl or heteroaryl which may optionallyinclude one or more of the same or different additional heteroatoms andwhich is optionally substituted with one or more of the same ordifferent R^(a) or suitable R^(b) groups;

each R^(d) is independently R^(a);

each m is independently an integer from 1 to 3; and

each n is independently an integer from 0 to 3.

In the compounds of structural formula (I), L¹ and L² represent,independently of one another, a direct bond or a linker. Thus, as willbe appreciated by skilled artisans, the substituents R² and/or R⁴ may bebonded either directly to their respective nitrogen atoms or,alternatively, spaced away from their respective nitrogen atoms by wayof a linker. The identity of the linker is not critical and typicalsuitable linkers include, but are not limited to, (C1-C6) alkyldiyls,(C1-C6) alkanos and (C1-C6) heteroalkyldiyls, each of which may beoptionally substituted with one or more of the same or different R⁸groups, where R⁸ is as previously defined for structural formula (I). Ina specific embodiment, L¹ and L² are each, independently of one another,selected from the group consisting of a direct bond, (C1-C3) alkyldiyloptionally substituted with one or more of the same or different R^(a),suitable R^(b) or R⁹ groups and 1-3 membered heteroalkyldiyl optionallysubstituted with one or more of the same or different R^(a), suitableR^(b) or R⁹ groups, wherein R⁹ is selected from the group consisting of(C1-C3) alkyl, —OR^(a), —C(O)OR^(a), (C5-C10) aryl optionallysubstituted with one or more of the same or different halogens, phenyloptionally substituted with one or more of the same or differenthalogens, 5-10 membered heteroaryl optionally substituted with one ormore of the same or different halogens and 6 membered heteroaryloptionally substituted with one or more of the same or differenthalogens; and R^(a) and R^(b) are as previously defined for structuralformula (I). Specific R⁹ groups that may be used to substitute L¹ and L²include —OR^(a), —C(O)OR^(a), phenyl, halophenyl and 4-halophenyl,wherein R^(a) is as previously defined for structural formula (I).

In another specific embodiment, L¹ and L² are each, independently of oneanother, selected from the group consisting of methano, ethano andpropano, each of which may be optionally monosubstituted with an R⁹group, where R⁹ is as previously defined above.

In all of the above embodiments, specific R^(a) groups that may beincluded in R⁹ groups are selected from the group consisting ofhydrogen, (C1-C6) alkyl, phenyl and benzyl.

In still another specific embodiment, L¹ and L² are each a direct bondsuch that the 2,4-pyrimidinediamine compounds of the invention arecompounds according to structural formula (Ia):

including salts, hydrates, solvates and N-oxides thereof, wherein R²,R⁴, R⁵ and R⁶ are as previously defined for structural formula (I).Additional specific embodiments of the 2,4-pyrimidinediamine compoundsof the invention are described below.

In a first embodiment of the compounds of structural formula (I) and(Ia), L¹, L², R⁵, R⁶, R⁸, R^(a), R^(b), R^(c), R^(d), m and n are aspreviously defined, R² is

wherein each R³¹, independently of the others, is methyl or (C1-C6)alkyl and R⁴ is

X is selected from the group consisting of N and CH, Y is selected fromthe group consisting of O, S, SO, SO₂, SONR³⁶, NH, NR³⁵ and NR³⁷, Z isselected from the group consisting of O, S, SO, SO₂, SONR³⁶, NH, NR³⁵and NR³⁷. Each R³⁵ is, independently of the others, selected from thegroup consisting of hydrogen and R⁸, or, alternatively, two R³⁵ bondedto the same carbon atom are taken together to form an oxo (═O), NH orNR³⁸ group and the other two R³⁵ are each, independently of one another,selected from the group consisting of hydrogen and R⁸. Each R³⁶ isindependently selected from the group consisting of hydrogen and (C1-C6)alkyl. Each R³⁷ is independently selected from the group consisting ofhydrogen and a progroup. R³⁸ is selected from the group consisting of(C1-C6) alkyl and (C5-C14) aryl.

In particular, Y is O, Z is NH and X is N. R⁵ can be halogen and R⁶ is ahydrogen.

In a second embodiment of the compounds of structural formula (I) and(Ia), L¹, L², R⁵, R⁶, R⁸, R^(a), R^(b), R^(c), R^(d), m, n, R³⁵, R³⁶,R³⁷, R³⁸, X, Y and Z are as previously defined, R² is

wherein each R³¹, independently of the others, is methyl or (C1-C6)alkyl and R⁴ is

In particular, Y is O, Z is NH and X is N. R⁵ can be halogen and R⁶ is ahydrogen. In one particular aspect, Y is O, Z is NH, X is N and each R³¹is methyl.

In a third embodiment of the compounds of structural formula (I) and(Ia), L¹, L², R⁵, R⁶, R⁸, R^(a), R^(b), R^(c), R^(d), m, n,R³¹, R³⁵,R³⁶, R³⁷, R³⁸, X, Y and Z are as previously defined, R² is

and R⁴ is

and yy is 1-6. In particular, Y is O, Z is NH and X is N. R⁵ can behalogen and R⁶ is a hydrogen.

In a fourth embodiment of the compounds of structural formula (I) and(Ia), L¹, L², R⁵, R⁶, R⁸, R^(a), R^(b), R^(c), R^(d), m, n, R³⁵, R³⁶,R³⁷, R³⁸, X, Y and Z are as previously defined, R² is

and R⁴ is

Substitution about the R² phenyl ring can be at the 2, 3, 4, 5 or 6positions. In particular, Y is O, Z is NH and X is N. R⁵ can be halogenand R⁶ is a hydrogen.

In a fifth embodiment of the compounds of structural formula (I) and(Ia), L¹, L², R⁵, R⁶, R⁸, R^(a), R^(b), R^(c), R^(d), m, n, R³⁵, R³⁶,R³⁷, R³⁸, X, Y and Z are as previously defined, R² is a phenyl groupdisubstituted with two R^(b) groups and R⁴ is

Substitution about the R² phenyl ring can be at the 2,3, 2,4, 2, 5, 2,6,3,4, 3,5, 3,6, 4,5, 4,6 or 5,6 positions, with the proviso that thefollowing compounds are not included:

-   N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;-   N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;-   N2-(3,4-Dichlorophenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine;-   N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-(3-fluoro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;-   N2-(3,5-Dichlorophenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine;    and-   N2-(3-Chloro-4-trifluoromethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.

In particular, Y is O, Z is NH and X is N. R⁵ can be halogen and R⁶ is ahydrogen. In certain aspects, each R^(b) independently is selected from(C1-C6) alkoxy, (C1-16) alkyl, (C1-C6) perhaloalkyls, halogens,carboxylic acid, carboxylic ester, carboxamides, sulfonamides andimidazoles.

In a sixth embodiment of the compounds of structural formula (I) and(Ia), L¹, L², R⁵, R⁶, R⁸, R^(a), R^(b), R^(c), R^(d), m, n, R³⁵, R³⁶,R³⁷, R³⁸, X, Y and Z are as previously defined, R² is a phenyl grouptrisubstituted with three R^(b) groups and R⁴ is

Substitution about the R² phenyl ring can be at the 2,3,4, 2,3,5, 2,3,6,2,4,5, 2,4,6, 2,5,6, 3,4,5, 3,4,6, 3,5,6, or 4,5,6 positions, with theproviso that the following compounds are not included:

-   N2-(3-Chloro-4-methoxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine;-   N2-(3-Chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine;    and-   N2-(3,5-Dimethyl-4-methoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.

In particular, Y is 0, Z is NH and X is N. R⁵ can be halogen and R⁶ is ahydrogen. In certain aspects, each R^(b) independently is selected from(C1-C6) alkoxy, (C1-16) alkyl, (C1-C6) perhaloalkyls, halogens,carboxylic acid, carboxylic esters, carboxamides, sulfonamides

In certain embodiments, the compounds disclosed in U.S. patentapplication Ser. No. 10/631,029, filed on Jul. 29, 2003 and Ser. No.10/355,543, filed Jan. 31, 2003, respectively, are not included withinthe scope of the present application.

In a seventh embodiment of the compounds of structural formula (I) and(Ia), R⁵, R⁶, L¹ and L² are as previously defined, R² is selected fromthe group consisting of (C1-C6) alkyl optionally substituted with one ormore of the same or different R⁸ groups, (C3-C8) cycloalkyl optionallysubstituted with one or more of the same or different R⁸ groups,cyclohexyl optionally substituted with one or more of the same ordifferent R⁸ groups, 3-8 membered cycloheteroalkyl optionallysubstituted with one or more of the same or different R⁸ groups,(C5-C15) aryl optionally substituted with one or more of the same ordifferent R⁸ groups, phenyl optionally substituted with one or more ofthe same or different R⁸ groups and 5-15 membered heteroaryl optionallysubstituted with one or more of the same or different R⁸ groups, R⁴ is

R^(6a) is (C5-C10) aryl optionally substituted with one or more of thesame or different R⁸ groups or phenyl optionally substituted with one ormore of the same or different R⁸ groups and R⁸ is as previously defined.

In an eight embodiment of the compounds of structural formulae (I) and(Ia), R⁵, R⁶, R⁸, L¹ and L² are as previously defined, R² is selectedfrom the group consisting of

wherein each R²¹ is independently a halogen atom or an alkyl optionallysubstituted with one or more of the same or different halo groups, R²²and R²³ are each, independently of one another, a hydrogen atom, methylor ethyl group optionally substituted with one or more of the same ordifferent halo groups and R⁴ is a (C3-C8) cycloalkyl optionallysubstituted with one or more of the same or different R⁸ groups.

In a ninth embodiment of the compounds of structural formulae (I) and(Ia), R⁵, R⁶, R⁸, L¹ and L² are as previously defined, R² is selectedfrom the group consisting of (C1-C6) alkyl optionally substituted withone or more of the same or different R⁸ groups, (C3-C8) cycloalkyloptionally substituted with one or more of the same or different R⁸groups, cyclohexyl optionally substituted with one or more of the sameor different R⁸ groups, 3-8 membered cycloheteroalkyl optionallysubstituted with one or more of the same or different R⁸ groups,(C5-C15) aryl optionally substituted with one or more of the same ordifferent R⁸ groups, phenyl optionally substituted with one or more ofthe same or different R⁸ groups and 5-15 membered heteroaryl optionallysubstituted with one or more of the same or different R⁸ groups, R⁴ is

R³⁵ is a hydrogen or R⁸; and

R⁴⁵ is a (C3-C8) cycloalkyl optionally substituted with one or more ofthe same or different R⁸ groups.

In a tenth embodiment compounds of structural formulae

R² selected from the group consisting of (C1-C6) alkyl optionallysubstituted with one or more of the same or different R⁸ groups, (C3-C8)cycloalkyl optionally substituted with one or more of the same ordifferent R⁸ groups, cyclohexyl optionally substituted with one or moreof the same or different R⁸ groups, 3-8 membered cycloheteroalkyloptionally substituted with one or more of the same or different R⁸groups, (C5-C15) aryl optionally substituted with one or more of thesame or different R⁸ groups, phenyl optionally substituted with one ormore of the same or different R⁸ groups and 5-15 membered heteroaryloptionally substituted with one or more of the same or different R⁸groups, R⁴ is selected from the group consisting of hydrogen, (C1-C6)alkyl optionally substituted with one or more of the same or differentR⁸ groups, (C3-C8) cycloalkyl optionally substituted with one or more ofthe same or different R⁸ groups, cyclohexyl optionally substituted withone or more of the same or different R⁸ groups, 3-8 memberedcycloheteroalkyl optionally substituted with one or more of the same ordifferent R⁸ groups, (C5-C15) aryl optionally substituted with one ormore of the same or different R⁸ groups, phenyl optionally substitutedwith one or more of the same or different R⁸ groups and 5-15 memberedheteroaryl optionally substituted with one or more of the same ordifferent R⁸ groups, and R⁵⁵ is selected from the group consisting of(C1-C6) alkyl optionally substituted with one or more of the same ordifferent R⁸ groups, (C3-C8) cycloalkyl optionally substituted with oneor more of the same or different R⁸ groups, cyclohexyl optionallysubstituted with one or more of the same or different R⁸ groups, 3-8membered cycloheteroalkyl optionally substituted with one or more of thesame or different R⁸ groups, (C5-C15) aryl optionally substituted withone or more of the same or different R⁸ groups, phenyl optionallysubstituted with one or more of the same or different R⁸ groups and 5-15membered heteroaryl optionally substituted with one or more of the sameor different R⁸ groups.

In an eleventh embodiment of the compounds of structural formulae (I)and (Ia), R⁵, R⁶, R⁸, L¹ and L² are as previously defined, R² is

and R⁴ is selected from the group consisting of hydrogen, (C1-C6) alkyloptionally substituted with one or more of the same or different R⁸groups, (C3-C8) cycloalkyl optionally substituted with one or more ofthe same or different R⁸ groups, cyclohexyl optionally substituted withone or more of the same or different R⁸ groups, 3-8 memberedcycloheteroalkyl optionally substituted with one or more of the same ordifferent R⁸ groups, (C5-C15) aryl optionally substituted with one ormore of the same or different R⁸ groups, phenyl optionally substitutedwith one or more of the same or different R⁸ groups and 5-15 memberedheteroaryl optionally substituted with one or more of the same ordifferent R⁸ groups.

In a twelfth embodiment of the compounds of structural formulae (I) and(Ia), R⁵, R⁶, R⁸, L¹ and L² are as previously defined, R² is

R⁴ is selected from the group consisting of hydrogen, (C1-C6) alkyloptionally substituted with one or more of the same or different R⁸groups, (C3-C8) cycloalkyl optionally substituted with one or more ofthe same or different R⁸ groups, cyclohexyl optionally substituted withone or more of the same or different R⁸ groups, 3-8 memberedcycloheteroalkyl optionally substituted with one or more of the same ordifferent R⁸ groups, (C5-C15) aryl optionally substituted with one ormore of the same or different R⁸ groups, phenyl optionally substitutedwith one or more of the same or different R⁸ groups and 5-15 memberedheteroaryl optionally substituted with one or more of the same ordifferent R⁸ groups and each R³⁵ individually is a hydrogen or asuitable R⁸.

In a thirteenth embodiment of the compounds of structural formulae (I)and (Ia), R⁵, R⁶, R⁸, L¹ and L² are as previously defined, R² isselected from the group consisting of (C1-C6) alkyl optionallysubstituted with one or more of the same or different R⁸ groups, (C3-C8)cycloalkyl optionally substituted with one or more of the same ordifferent R⁸ groups, cyclohexyl optionally substituted with one or moreof the same or different R⁸ groups, 3-8 membered cycloheteroalkyloptionally substituted with one or more of the same or different R⁸groups, (C5-C15) aryl optionally substituted with one or more of thesame or different R⁸ groups, phenyl optionally substituted with one ormore of the same or different R⁸ groups and 5-15 membered heteroaryloptionally substituted with one or more of the same or different R⁸groups, R⁴ is

and R³⁵ is a hydrogen or a suitable R⁸.

In a fourteenth embodiment, the compounds of structural formulae (I) and(Ia), R⁵, R⁶, R⁸, L¹ and L² are as previously defined, R⁴ is asubstituted phenyl group, substituted with the same or different R⁸groups and R² is

wherein “yy”=1 to 6. In one aspect, the R⁴ phenyl group is di or trisubstituted with the same or different R⁸ groups, and in particular,halogen atoms. In particular, R⁴ can be substituted at the 3 and 4positions relative to attachment to the N4 amine, particularly withhalogen atoms and/or alkoxy groups.

In a fifteenth embodiment, the compounds of structural formulae (I) and(Ia), R⁵, R⁶, R⁸, L¹ and L² are as previously defined, R⁴ is asubstituted phenyl group, substituted with the same or different R⁸groups and R² is

In one aspect, the R⁴ phenyl group is di or tri substituted with thesame or different R⁸ groups, and in particular, halogen atoms. Inparticular, R⁴ can be substituted at the 3 and 4 positions relative toattachment to the N4 amine, particularly with halogen atoms and/oralkoxy groups.

In a sixteenth embodiment, the compounds of structural formulae (I) and(Ia), R⁵, R⁶, R⁸, L¹ and L² are as previously defined, R⁴ is asubstituted phenyl group, substituted with the same or different R⁸groups and R² is

In one aspect, the R⁴ phenyl group is di or tri substituted with thesame or different R⁸ groups, and in particular, halogen atoms. Inparticular, R⁴ can be substituted at the 3 and 4 positions relative toattachment to the N4 amine, particularly with halogen atoms and/oralkoxy groups.

In a seventeenth embodiment, the compounds of structural formulae (I)and (Ia), R⁵, R⁶, R⁸, L¹ and L² are as previously defined, R⁴ is asubstituted phenyl group, substituted with the same or different R⁸groups and R² is

wherein R³⁵ is an alkylalkoxy group, and in particular is

In one aspect, the R⁴ phenyl group is di or tri substituted with thesame or different R⁸ groups, and in particular, halogen atoms. Inparticular, R⁴ can be substituted at the 3 and 4 positions relative toattachment to the N4 amine, particularly with halogen atoms and/oralkoxy groups.

In a eighteenth embodiment, the compounds of structural formulae (I) and(Ia), R⁵, R⁶, R⁸, L¹ and L² are as previously defined, R⁴ is asubstituted phenyl group, substituted with the same or different R⁸groups and R² is

wherein R³⁵ is an alkyl group, and in particular is

In one aspect, the R⁴ phenyl group is di or tri substituted with thesame or different R⁸ groups, and in particular, halogen atoms. Inparticular, R⁴ can be substituted at the 3 and 4 positions relative toattachment to the N4 amine, particularly with halogen atoms and/oralkoxy groups.

In a nineteenth embodiment, the compounds of structural formulae (I) and(Ia), R⁵, R⁶, R⁸, L¹ and L² are as previously defined R⁴ is

and R² is

and in particular, is substituted at the 3 or 4 position with theisoxazole. Y is selected from the group consisting of O, S, SO, SO₂,SONR³⁶, NH and NR³⁷. Z is selected from the group consisting of O, S,SO, SO₂, SONR³⁶, NH and NR³⁷. Each R³⁵ is, independently of the others,selected from the group consisting of hydrogen and R⁸, or,alternatively, two R³⁵ bonded to the same carbon atom are taken togetherto form an oxo (═O), NH or NR³⁸ group and the other two R³⁵ each, ifpresent, independently of one another, are selected from the groupconsisting of hydrogen and R⁸. Each R³⁶ is independently selected fromthe group consisting of hydrogen and (C1-C6) alkyl. Each R³⁷ isindependently selected from the group consisting of hydrogen and aprogroup. R³⁸ is selected from the group consisting of (C1-C6) alkyl and(C5-C14) aryl.

In certain aspects, R³⁷ is selected from the group consisting of aryl,arylalkyl, heteroaryl, R^(a), R^(b)—CR^(a)R^(b)—O—C(O)R⁸,—CR^(a)R^(b)—O—PO(OR⁸)₂, —CH₂—O—PO(OR⁸)₂, —CH₂—PO(OR⁸)₂,—C(O)—CR^(a)R^(b)—N(CH₃)₂, —CR^(a)R^(b)—O—C(O)—CR^(a)R^(b)—N(CH₃)₂,—C(O)R⁸, —C(O)CF₃ and —C(O)—NR⁸—C(O)R⁸

In one aspect, Y is oxygen, Z is NH and one or more of R³⁵ is an alkylgroup, and in particular, a methyl group. In certain, two R³⁵'s form agem dialkyl moiety, in particular, a gem dimethyl moiety adjacent to theNH depicted as

In a twentieth embodiment, the compounds of structural formulae (I) and(Ia), R⁵, R⁶, R⁸, L¹ and L² are as previously defined, R⁴ is

wherein each R³⁵ are as defined above, and in particular are bothhalogen atoms, e.g., fluorine, and R² is a substituted phenyl group,substituted with the same or different R⁸ groups. In one aspect, the R²phenyl group is di or tri substituted with the same or different R⁸groups, and in particular, halogen atoms. In particular, R² can besubstituted at the 3 and 5 positions relative to attachment to the N2amine, particularly with halogen atoms and/or alkoxy groups.

In a twenty first embodiment, the compounds of structural formulae (I)and (Ia), R⁵, R⁶, R⁸, L¹ and L² are as previously defined, R⁴ is

wherein Y and Z are defined as above and R² is

and in particular is substituted at the 3 or 4 position with theisoxazole. In one aspect of the thirty ninth embodiment with regard toR⁴, Y is NH and Z is O, e.g.,

In a twenty second embodiment the compounds of structural formulae (I)and (Ia), R⁵, R⁶, R⁸, L¹ and L² are as previously defined, R⁴ is

wherein R⁸ and R^(c) are as defined above and R² is a phenyl groupsubstituted at the 3 or 4 position with

In one aspect —OR⁸, R⁸ is a hydrogen atom.

In a twenty third embodiment, the compounds of structural formulae (I)and (Ia), R⁵, R⁶, R⁸, L¹ and L² are as previously defined, R⁴ is

and R² is a substituted phenyl group, substituted with at least two ofthe same or different R⁸ groups as defined above. Suitable examplesinclude compounds 340, 343, 349, 350 and 351.

In a twenty fourth embodiment, the compounds of structural formulae (I)and (Ia), R⁵, R⁶, R⁸, L¹ and L² are as previously defined, R⁴ is

and R² is

In a twenty fifth embodiment, the compounds of structural formulae (I)and (Ia), R⁵, R⁶, R⁸, L¹ and L² are as previously defined, R⁴ is

and R² is

wherein Y and R³⁵ are as defined above. Suitable examples includecompounds 368, 381, 382, 383 and 384.

In a twenty sixth embodiment, the compounds of structural formulae (I)and (Ia), R⁵, R⁶, R⁸, L¹ and L² are as previously defined, R⁴ isselected from the group consisting of (C1-C6) alkyl optionallysubstituted with one or more of the same or different R⁸ groups, (C3-C8)cycloalkyl optionally substituted with one or more of the same ordifferent R⁸ groups, cyclohexyl optionally substituted with one or moreof the same or different R⁸ groups, 3-8 membered cycloheteroalkyloptionally substituted with one or more of the same or different R⁸groups, (C5-C15) aryl optionally substituted with one or more of thesame or different R⁸ groups, phenyl optionally substituted with one ormore of the same or different R⁸ groups and 5-15 membered heteroaryloptionally substituted with one or more of the same or different R⁸groups and R² is

wherein R³⁵ is as defined above. Suitable examples include compounds 205and 206.

In a twenty seventh embodiment the compounds of structural formulae (I)and (Ia), R⁵, R⁶, R⁸, L¹ and L² are as previously defined, R⁴ is

and R² is a phenyl group substituted with one or more of the same R⁸groups. Suitable examples include compounds 328, 329, 330, 341, 553,554, 555, 556, 559 and 560.

In a twenty eighth embodiment, the compounds of structural formulae (I)and (Ia), R⁵, R⁶, R⁸, L¹, and L² are as previously defined, R⁴ isselected from the group consisting of (C1-C6) alkyl optionallysubstituted with one or more of the same or different R⁸ groups, (C3-C8)cycloalkyl optionally substituted with one or more of the same ordifferent R⁸ groups, cyclohexyl optionally substituted with one or moreof the same or different R⁸ groups, 3-8 membered cycloheteroalkyloptionally substituted with one or more of the same or different R⁸groups, (C5-C15) aryl optionally substituted with one or more of thesame or different R⁸ groups, phenyl optionally substituted with one ormore of the same or different R⁸ groups and 5-15 membered heteroaryloptionally substituted with one or more of the same or different R⁸groups and R² is

wherein Y is as defined above or is NR³⁵ and R³⁵ is as defined above.Suitable examples include compounds 1070, 1071, 1073, 1074, 1075, 1076,1078, 1080, 1085, 1091 and 1092.

In a twenty ninth embodiment, the compounds of structural formulae (I)and (Ia), R⁵, R⁶, R⁸, L¹ and L² are as previously defined, R⁴ is

wherein R² is a substituted phenyl group or an indazole, substitutedwith one or more of the same or different R⁸ groups as defined above.Suitable examples include compounds 1251, 1252, 1253, 1254 and 1255.

In a thirtieth embodiment, the compounds of structural formulae (I) and(Ia), R⁵, R⁶, R⁸, L¹ and L² are as previously defined, R⁴ is

wherein each R³⁵ independently is as described above and R² is

Suitable examples include compounds 217, 218, 219, 220, 221, 222, 223,224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 236, 237, 238,239, 240, 241, 242, 243, 244, 245, 246, 247, 1281, 1283, 1283, 1284,1285, 1287, 1288, 1289, 1290 and 1291.

In a thirty first embodiment, the compounds of structural formulae (I)and (Ia), R⁵, R⁶, R⁸, L¹ and L² are as previously defined, R⁴ is

wherein R^(z) is a hydrogen or lower alkyl group, R^(x) and R^(y) areeach independently lower alkyl groups, or taken together form acycloalkyl and R^(p) is a halogen atom or a lower alkyl group and R² isas defined above. Suitable examples include compounds 402, 403, 407,408, 409 and 410.

In a thirty second embodiment, the compounds of structural formulae (I)and (Ia), R⁵, R⁶, R⁸, L¹ and L² are as previously defined, R² is

and R⁴ is

R¹¹ and R¹² are each, independently of one another, selected from thegroup consisting of alkyl, alkoxy, halogen, haloalkoxy, aminoalkyl andhydroxyalkyl;

In a thirty third embodiment, the compounds of structural formulae (I)and (Ia), R⁵, R⁶, R⁸, L¹ and L² are as previously defined, R² isselected from (C1-C6) alkyl optionally substituted with one or more ofthe same or different R⁸ groups, (C3-C8) cycloalkyl optionallysubstituted with one or more of the same or different R⁸ groups,cyclohexyl optionally substituted with one or more of the same ordifferent R⁸ groups, 3-8 membered cycloheteroalkyl optionallysubstituted with one or more of the same or different R⁸ groups,(C5-C15) aryl optionally substituted with one or more of the same ordifferent R⁸ groups, phenyl optionally substituted with one or more ofthe same or different R⁸ groups and 5-15 membered heteroaryl optionallysubstituted with one or more of the same or different R⁸ groups,

R⁵, R⁶, R⁸, R^(a), R^(b), R^(c), R^(d), m and n are as described above;

each R²¹, R²² and R²³ are each, independently of one another, asdescribed above and in particular, an alkyl group;

each R²⁸ individually is a halogen or alkoxy;

R²⁹ is a (C1-C6) alkyl or (C3-C9) cycloalkyl;

R³⁰ is an alkyl group or a halogen; X is selected from the groupconsisting of N and CH;

Y, Z, R³⁵, R³⁶, R³⁷ and R³⁸ are as described above;

each R⁴⁶, R⁴⁷ and R⁴⁸ independently is selected from the groupconsisting of a hydrogen, alkyl, alkoxy, hydroxyl, halogen, isoxazole,piperazino, N-alkyl piperazine, morpholino and CH₃NHC(O)CH₂O—, with theproviso that R⁴⁶, R⁴⁷ and R⁴⁸ are all not hydrogen and when one of R⁴⁶,R⁴⁷ or R⁴⁸ is isoxazole, piperazino, N-alkyl piperazine, morpholino orCH₃NHC(O)CH₂O—, then the remaining R⁴⁶, R⁴⁷ or R⁴⁸ are hydrogen;

R⁵⁰ is an alkyl group or —(CH₂)_(q)OH;

q is an integer from 1 to 6;

R⁵² is an alkyl group or a substituted alkyl group

p is 1, 2 or 3; and

x=1-8.

In a thirty fourth embodiment of the compounds of structural formulae(I) and (Ia), R², R⁴, R⁵, L¹ and L² are as previously described fortheir respective structures (I) and (Ia), with the proviso that R² isnot 3,4,5-trimethoxyphenyl, 3,4,5-tri (C1-C6) alkoxyphenyl or

where R²¹, R²² and R²³ are as defined for R¹, R² and R³, respectively ofU.S. Pat. No. 6,235,746, the disclosure of which is incorporated byreference. In a specific embodiment of this first embodiment, R²¹ ishydrogen, halo, straight-chain or branched (C1-C6) alkyl optionallysubstituted with one or more of the same or different R²⁵ groups,hydroxyl, (C1-C6) alkoxy optionally substituted with one or more of thesame or different phenyl or R²⁵ groups, thiol (—SH), (C1-C6) alkylthiooptionally substituted with one or more of the same or different phenylor R²⁵ groups, amino (—NH₂), —NHR²⁶ or —NR²⁶R²⁶; R²² and R²³ are each,independently of one another, a (C1-C6) straight-chain or branched alkyloptionally substituted with one or more of the same or different R²⁵groups; R²⁵ is selected from the group consisting of halo, hydroxyl,(C1-C6) alkoxy, thiol, (C1-C6) alkylthio, (C1-C6) alkylamino and (C1-C6)dialkylamino; and each R²⁶ is independently a (C1-C6) alkyl optionallysubstituted with one or more of the same or different phenyl or R²⁵groups or a —C(O)R²⁷, where R²⁷ is a (C1-C6) alkyl optionallysubstituted with one or more of the same or different phenyl or R²⁵groups.

In another specific embodiment, R²¹ is methoxy optionally substitutedwith one or more of the same or different halo groups and/or R²² and R²³are each, independently of one another, a methyl or ethyl optionallysubstituted with one or more of the same or different halo groups.

In a thirty fifth embodiment, the compounds of structural formulae (I)and (Ia), R⁵, R⁶, R⁸, L¹ and L² are as previously defined:

R² is

R⁴ is

R⁵, R⁶, R³⁰, R³⁵ and x are as defined above. In certain embodiments, xis 2 through 4. In other embodiments, R³⁵ is a methyl group. In stilladditional embodiments, R³⁰ is chlorine, methyl or trifluoromethyl. Instill other embodiments, R⁵ is fluorine and R⁶ is hydrogen.

In a thirty sixth embodiment the 2,4-pyrimidinediamine includes thosecompounds according to structures I and I(a) wherein R² is selected fromthe group consisting of (C1-C6) alkyl optionally substituted with one ormore of the same or different R⁸ groups, (C3-C8) cycloalkyl optionallysubstituted with one or more of the same or different R⁸ groups,cyclohexyl optionally substituted with one or more of the same ordifferent R⁸ groups, 3-8 membered cycloheteroalkyl optionallysubstituted with one or more of the same or different R⁸ groups,(C5-C15) aryl optionally substituted with one or more of the same ordifferent R⁸ groups, phenyl optionally substituted with one or more ofthe same or different R⁸ groups and 5-15 membered heteroaryl optionallysubstituted with one or more of the same or different R⁸ groups. R⁴ is

R⁵, R⁶ and R⁸ are described as above. In certain embodiments, R⁵ is afluorine atom and R⁶ is a hydrogen atom. In certain embodiments, R² is adi or tri-substituted phenyl group.

In a thirty seventh embodiment, the invention pertains to2,4-pyrimidinediamine compounds according to structures I and I(a)wherein R² is

R⁴ is

and R⁵, R⁶, R²² and R²³, R⁴⁶, R⁴⁷ and R⁴⁸ are as defined above, eachR²¹, independently of one another, is an alkyl group. In certainembodiments, R⁵ is a fluorine atom and R⁶ is a hydrogen atom.

In a thirty eighth embodiment, the present invention relates to2,4-pyrimidinediamine compounds according to structures I and I(a)wherein R² is

R⁴ is,

R⁵, R⁶, R⁸, R²¹, R²³, R²⁸, R³⁵, R³⁶, R³⁷, R³⁸, Y, Z, R^(a), R^(b),R^(c), R^(d), m and n are as described above, and X is selected from thegroup consisting of N and CH. In a particular embodiment, R²⁸ is amethoxy. In another embodiment, R²³ is methyl. In particularembodiments, R²¹ is a methyl group. In other embodiments, each R²⁸ ischlorine. In still additional embodiments, R²¹ is a methyl group and atleast one R²⁸ is a chlorine. In another embodiment, R²⁸ is a methoxy.

In a thirty ninth embodiment, the present invention providespyrimidinediamine compounds according to structures I and I(a) whereinR² is

R⁴ is,

R⁵, R⁶, R⁸, R²¹, each R²⁸, R²⁹, R^(a), R^(b), R^(c), R^(d), m and n, X,Y, Z, each R³⁵, each R³⁶, each R³⁷ and R³⁸ are as described above.

In certain embodiments, R²⁹ is a t-butyl group. In other embodiments,R²¹ is a methyl group. In certain embodiments, each R²⁸ is a chlorine.In still another embodiment, R²¹ is a methyl group and at least one ofR²⁸ is a chlorine.

In a fortieth embodiment, the invention pertains to2,4-pyrimidinediamine compounds according to structures I and I(a)wherein R² is

R⁴ is

R⁵, R⁶, R⁸, R²¹, each R²⁸, R^(a), R^(b), R^(c), m, n, p, X, Y, Z, eachR³⁵,each R³⁶, each R³⁷ and R³⁸ are as described above. In particularembodiments, R²¹ is a methyl group. In other embodiments, each R²⁸ is achlorine. In still other embodiments, R²¹ is a methyl group and at leastone of R²⁸ is a chlorine. In still another aspect, p is 1 or 2.

In a forty first embodiment, the invention relates to2,4-pyrimidinediamine compounds according to structures I and I(a)wherein R² is

R⁴ is

R⁵, R⁶, R⁸, R²¹, each R²⁸, R^(a), R^(b), R^(c). R^(d), m, n, q, X, Y, Z,R³⁵, R³⁶, R³⁷, R³⁸, R⁵⁰ and R⁵² are as described above.

In certain aspects, R⁵⁰ is —CH₂CH₂—OH or methyl. In another aspect, R⁵²is trifluoromethyl. In still another aspect, at least one R²⁸ is achlorine. In yet another aspect, R⁵⁰ is a methyl and at least one R²⁸ isa chlorine.

In a forty second embodiment, applicable to the first through fortyfirst embodiments, R⁵ of the pyrimidine ring is a halogen atom, such asfluorine, and R⁶ of the pyrimidine ring is a hydrogen atom.

In a forty third embodiment, L¹ and L² are covalent bonds for theabove-identified embodiments.

Also specifically described are combinations of the above first throughforty third embodiments.

Those of skill in the art will appreciate that the 2,4-pyrimidinediaminecompounds described herein may include functional groups that can bemasked with progroups to create prodrugs. Such prodrugs are usually, butneed not be, pharmacologically inactive until converted into theiractive drug form. Indeed, many of the active 2,4-pyrimidinediaminecompounds described in TABLE 1, include promoieties that arehydrolyzable or otherwise cleavable under conditions of use. Forexample, ester groups commonly undergo acid-catalyzed hydrolysis toyield the parent carboxylic acid when exposed to the acidic conditionsof the stomach, or base-catalyzed hydrolysis when exposed to the basicconditions of the intestine or blood. Thus, when administered to asubject orally, 2,4-pyrimidinediamines that include ester moieties maybe considered prodrugs of their corresponding carboxylic acid,regardless of whether the ester form is pharmacologically active.Referring to TABLE 1, numerous ester-containing 2,4-pyrimidinediaminesof the invention are active in their ester, “prodrug” form.

In the prodrugs of the invention, any available functional moiety may bemasked with a progroup to yield a prodrug. Functional groups within the2,4-pyrimidinediamine compounds that may be masked with progroups forinclusion in a promoiety include, but are not limited to, amines(primary and secondary), hydroxyls, sulfanyls (thiols), carboxyls, etc.Myriad progroups suitable for masking such functional groups to yieldpromoieties that are cleavable under the desired conditions of use areknown in the art. All of these progroups, alone or in combinations, maybe included in the prodrugs of the invention.

In one illustrative embodiment, the prodrugs of the invention arecompounds according to structural formula (I) in which R^(c) and R^(d)may be, in addition to their previously-defined alternatives, aprogroup.

Those of skill in the art will appreciate that many of the compounds andprodrugs of the invention, as well as the various compound speciesspecifically described and/or illustrated herein, may exhibit thephenomena of tautomerism, conformational isomerism, geometric isomerismand/or optical isomerism. For example, the compounds and prodrugs of theinvention may include one or more chiral centers and/or double bonds andas a consequence may exist as stereoisomers, such as double-bond isomers(i.e., geometric isomers), enantiomers and diasteromers and mixturesthereof, such as racemic mixtures. As another example, the compounds andprodrugs of the invention may exist in several tautomeric forms,including the enol form, the keto form and mixtures thereof. As thevarious compound names, formulae and compound drawings within thespecification and claims can represent only one of the possibletautomeric, conformational isomeric, optical isomeric or geometricisomeric forms, it should be understood that the invention encompassesany tautomeric, conformational isomeric, optical isomeric and/orgeometric isomeric forms of the compounds or prodrugs having one or moreof the utilities described herein, as well as mixtures of these variousdifferent isomeric forms. In cases of limited rotation around the2,4-pyrimidinediamine core structure, atropisomers are also possible andare also specifically included in the compounds of the invention.

Moreover, skilled artisans will appreciate that when lists ofalternative substituents include members which, owing to valencyrequirements or other reasons, cannot be used to substitute a particulargroup, the list is intended to be read in context to include thosemembers of the list that are suitable for substituting the particulargroup. For example, skilled artisans will appreciate that while all ofthe listed alternatives for R^(b) can be used to substitute an alkylgroup, certain of the alternatives, such as ═O, cannot be used tosubstitute a phenyl group. It is to be understood that only possiblecombinations of substituent-group pairs are intended.

The compounds and/or prodrugs of the invention may be identified byeither their chemical structure or their chemical name. When thechemical structure and the chemical name conflict, the chemicalstructure is determinative of the identity of the specific compound.

Depending upon the nature of the various substituents, the2,4-pyrimidinediamine compounds and prodrugs of the invention may be inthe form of salts. Such salts include salts suitable for pharmaceuticaluses (“pharmaceutically-acceptable salts”), salts suitable forveterinary uses, etc. Such salts may be derived from acids or bases, asis well-known in the art.

In one embodiment, the salt is a pharmaceutically acceptable salt.Generally, pharmaceutically acceptable salts are those salts that retainsubstantially one or more of the desired pharmacological activities ofthe parent compound and which are suitable for administration to humans.Pharmaceutically acceptable salts include acid addition salts formedwith inorganic acids or organic acids. Inorganic acids suitable forforming pharmaceutically acceptable acid addition salts include, by wayof example and not limitation, hydrohalide acids (e.g., hydrochloricacid, hydrobromic acid, hydriodic, etc.), sulfuric acid, nitric acid,phosphoric acid, and the like. Organic acids suitable for formingpharmaceutically acceptable acid addition salts include, by way ofexample and not limitation, acetic acid, trifluoroacetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalicacid, pyruvic acid, lactic acid, malonic acid, succinic acid, malicacid, maleic acid, fumaric acid, tartaric acid, citric acid, palmiticacid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid,mandelic acid, alkylsulfonic acids (e.g., methanesulfonic acid,ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonicacid, etc.), arylsulfonic acids (e.g., benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, cycloalkylsulfonic acids (e.g., camphorsulfonicacid), 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonicacid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylaceticacid, lauryl sulfuric acid, gluconic acid, glutamic acid,hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, andthe like.

Pharmaceutically acceptable salts also include salts formed when anacidic proton present in the parent compound is either replaced by ametal ion (e.g., an alkali metal ion, an alkaline earth metal ion or analuminum ion), an ammonium ion or coordinates with an organic base(e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine,morpholine, piperidine, dimethylamine, diethylamine, etc.).

The 2,4-pyrimidinediamine compounds and of the invention, as well as thesalts thereof, may also be in the form of hydrates, solvates andN-oxides, as are well-known in the art.

6.3 Methods of Synthesis

The compounds and prodrugs of the invention may be synthesized via avariety of different synthetic routes using commercially availablestarting materials and/or starting materials prepared by conventionalsynthetic methods. Suitable exemplary methods that may be routinelyadapted to synthesize the 2,4-pyrimidinediamine compounds and prodrugsof the invention are found in U.S. Pat. No. 5,958,935, U.S. patentapplication Ser. No. 10/355,543, filed Jan. 31, 2003 (US PublicationUS20040029902-A1), WO 03/063794, published Aug. 1, 2003, U.S. patentapplication Ser. No. 10/631,029, filed Jul. 29, 2003 and WO 2004/014382,published Feb. 19, 2004, the disclosures of which are incorporatedherein by reference. All of the compounds of structural formulae (I),(Ia) and (II) may be prepared by routine adaptation of these methods.

A variety of exemplary synthetic routes that can be used to synthesizethe 2,4-pyrimidinediamine compounds of the invention are described inSchemes (I)-(XI), below. In Schemes (I)-(XI), like-numbered compoundshave similar structures. These methods may be routinely adapted tosynthesize the prodrugs according to structural formula (II). In oneexemplary embodiment, the compounds can be synthesized from substitutedor unsubstituted uracils or thiouracils as illustrated in Scheme (I),below:

In Scheme (I), R², R⁴, R⁵, R⁶, L¹ and L² are as previously defined forstructural formula (I), X is a halogen (e.g., F, Cl, Br or I) and Y andY′ are each, independently of one another, selected from the groupconsisting of O and S. Referring to Scheme (I), uracil or thiouracil 2is dihalogenated at the 2- and 4-positions using standard halogenatingagent PDX3 (or other standard halogenating agent) under standardconditions to yield 2,4-bishalo pyrimidine 4. Depending upon the R⁵substituent, in pyrimidine 4, the halide at the C4 position is morereactive towards nucleophiles than the halide at the C2 position. Thisdifferential reactivity can be exploited to synthesize2,4-pyrimidinediamines according structural formula (I) by firstreacting 2,4-bishalopyrimidine 4 with one equivalent of amine 10,yielding 4N-substituted-2-halo-4-pyrimidineamine 8, followed by amine 6to yield a 2,4-pyrimidinediamine according structural formula (I).2N,4N-bis(substituted)-2,4-pyrimidinediamines 12 and 14 can be obtainedby reacting 2,4-bishalopyrimidine 4 with excess 6 or 10, respectively.

In most situations, the C4 halide is more reactive towards nucleophiles,as illustrated in the Scheme. However, as will be recognized by skilledartisans, the identity of the R⁵ substituent may alter this reactivity.For example, when R⁵ is trifluoromethyl, a 50:50 mixture of4N-substituted-4-pyrimidineamine 8 and the corresponding2N-substituted-2-pyrimidineamine is obtained. Regardless of the identityof the R⁵ substituent, the regioselectivity of the reaction can becontrolled by adjusting the solvent and other synthetic conditions (suchas temperature), as is well-known in the art.

The reactions depicted in Scheme (I) may proceed more quickly when thereaction mixtures are heated via microwave. When heating in thisfashion, the following conditions may be used: heat to 175° C. inethanol for 5-20 min. in a Smith Reactor (Personal Chemistry) in asealed tube (at 20 bar pressure).

The uracil or thiouracil 2 starting materials may be purchased fromcommercial sources or prepared using standard techniques of organicchemistry. Commercially available uracils and thiouracils that can beused as starting materials in Scheme (I) include, by way of example andnot limitation, uracil (Aldrich #13,078-8; CAS Registry 66-22-8);2-thio-uracil (Aldrich #11,558-4; CAS Registry 141-90-2);2,4-dithiouracil (Aldrich #15,846-1; CAS Registry 2001-93-6);5-acetouracil (Chem. Sources Int'l 2000; CAS Registry 6214-65-9);5-azidouracil; 5-aminouracil (Aldrich #85,528-6; CAS Registry 932-52-5);5-bromouracil (Aldrich #85,247-3; CAS Registry 51-20-7);5-(trans-2-bromovinyl)-uracil (Aldrich #45,744-2; CAS Registry69304-49-0); 5-(trans-2-chlorovinyl)-uracil (CAS Registry 81751-48-2);5-(trans-2-carboxyvinyl)-uracil; uracil-5-carboxylic acid(2,4-dihydroxypyrimidine-5-carboxylic acid hydrate; Aldrich #27,770-3;CAS Registry 23945-44-0); 5-chlorouracil (Aldrich #22,458-8; CASRegistry 1820-81-1); 5-cyanouracil (Chem. Sources Int'l 2000; CASRegistry 4425-56-3); 5-ethyluracil (Aldrich #23,044-8; CAS Registry4212-49-1); 5-ethenyluracil (CAS Registry 37107-81-6); 5-fluorouracil(Aldrich #85,847-1; CAS Registry 51-21-8); 5-iodouracil (Aldrich#85,785-8; CAS Registry 696-07-1); 5-methyluracil (thymine; Aldrich#13,199-7; CAS Registry 65-71-4); 5-nitrouracil (Aldrich #85,276-7; CASRegistry 611-08-5); uracil-5-sulfamic acid (Chem. Sources Int'l 2000;CAS Registry 5435-16-5); 5-(trifluoromethyl)-uracil (Aldrich #22,327-1;CAS Registry 54-20-6); 5-(2,2,2-trifluoroethyl)-uracil (CAS Registry155143-31-6); 5-(pentafluoroethyl)-uracil (CAS Registry 60007-38-3);6-aminouracil (Aldrich #A5060-6; CAS Registry 873-83-6)uracil-6-carboxylic acid (orotic acid; Aldrich #0-840-2; CAS Registry50887-69-9); 6-methyluracil (Aldrich #D11,520-7; CAS Registry 626-48-2);uracil-5-amino-6-carboxylic acid (5-aminoorotic acid; Aldrich #19,121-3;CAS Registry #7164-43-4); 6-amino-5-nitrosouracil(6-amino-2,4-dihydroxy-5-nitrosopyrimidine; Aldrich #27,689-8; CASRegistry 5442-24-0); uracil-5-fluoro-6-carboxylic acid (5-fluorooroticacid; Aldrich #42,513-3; CAS Registry 00000-00-0); anduracil-5-nitro-6-carboxylic acid (5-nitroorotic acid; Aldrich #18,528-0;CAS Registry 600779-49-9). Additional 5-, 6- and 5,6-substituted uracilsand/or thiouracils are available from General Intermediates of Canada,Inc., Edmonton, Alberta, Calif. (www.generalintermediates.com) and/orInterchim, France (www.interchim.com), or may be prepared using standardtechniques. Myriad textbook references teaching suitable syntheticmethods are provided infra.

Amines 6 and 10 may be purchased from commercial sources or,alternatively, may be synthesized utilizing standard techniques. Forexample, suitable amines may be synthesized from nitro precursors usingstandard chemistry. Specific exemplary reactions are provided in theExamples section. See also Vogel, 1989, Practical Organic Chemistry,Addison Wesley Longman, Ltd. and John Wiley & Sons, Inc.

Skilled artisans will recognize that in some instances, amines 6 and 10and/or substituents R⁵ and/or R⁶ on uracil or thiouracil 2 may includefunctional groups that require protection during synthesis. The exactidentity of any protecting group(s) used will depend upon the identityof the functional group being protected, and will be apparent to theseof skill in the art. Guidance for selecting appropriate protectinggroups, as well as synthetic strategies for their attachment andremoval, may be found, for example, in Greene & Wuts, Protective Groupsin Organic Synthesis, 3d Edition, John Wiley & Sons, Inc., New York(1999) and the references cited therein (hereinafter “Greene & Wuts”).

A specific embodiment of Scheme (I) utilizing 5-fluorouracil (Aldrich#32,937-1) as a starting material is illustrated in Scheme (Ia), below:

In Scheme (Ia), R², R⁴, L¹ and L² are as previously defined for Scheme(I). According to Scheme (Ia), 5-fluorouracil 3 is halogenated withPOCl₃ to yield 2,4-dichloro-5-fluoropyrimidine 5, which is then reactedwith excess amine 6 or 10 to yield N2,N4-bis substituted5-fluoro-2,4-pyrimidinediamine 11 or 13, respectively. Alternatively,non-bis 2N,4N-disubstituted-5-fluoro-2,4-pyrimidinediamine 9 may beobtained by reacting 2,4-dichloro-5-fluoropyrimidine 5 with oneequivalent of amine 10 (to yield2-chloro-N4-substituted-5-fluoro-4-pyrimidineamine 7) followed by one ormore equivalents of amine 6. In another exemplary embodiment, the2,4-pyrimidinediamine compounds of the invention may be synthesized fromsubstituted or unsubstituted cytosines as illustrated in Schemes (IIa)and (IIb), below:

In Schemes (IIa) and (IIb), R², R⁴, R⁵, R⁶, L¹, L² and X are aspreviously defined for Scheme (I) and PG represents a protecting group.Referring to Scheme (IIa), the C4 exocyclic amine of cytosine 20 isfirst protected with a suitable protecting group PG to yieldN4-protected cytosine 22. For specific guidance regarding protectinggroups useful in this context, see Vorbrüggen and Ruh-Pohlenz, 2001,Handbook of Nucleoside Synthesis, John Wiley & Sons, NY, pp. 1-631(“Vorbrüggen”). Protected cytosine 22 is halogenated at the C2 positionusing a standard halogenation reagent under standard conditions to yield2-chloro-4N-protected-4-pyrimidineamine 24. Reaction with amine 6followed by deprotection of the C4 exocyclic amine and reaction withamine 10 yields a 2,4-pyrimidinediamine according to structural formula(I).

Alternatively, referring to Scheme (IIb), cytosine 20 may be reactedwith amine 10 or protected amine 21 to yield N4-substituted cytosine 23or 27, respectively. These substituted cytosines may then be halogenatedas previously described, deprotected (in the case of N4-substitutedcytosine 27) and reacted with amine 6 to yield a 2,4-pyrimidinediamineaccording to structural formula (I).

Commercially-available cytosines that may be used as starting materialsin Schemes (IIa) and (IIb) include, but are not limited to, cytosine(Aldrich #14,201-8; CAS Registry 71-30-7); N⁴-acetylcytosine (Aldrich#37,791-0; CAS Registry 14631-20-0); 5-fluorocytosine (Aldrich#27,159-4; CAS Registry 2022-85-7); and 5-(trifluoromethyl)-cytosine.Other suitable cytosines useful as starting materials in Schemes (IIa)are available from General Intermediates of Canada, Inc., Edmonton,Alberta, Calif. (www.generalintermediates.com) and/or Interchim, France(www.interchim.com), or may be prepared using standard techniques.Myriad textbook references teaching suitable synthetic methods areprovided infra.

In still another exemplary embodiment, the 2,4-pyrimidinediaminecompounds of the invention may be synthesized from substituted orunsubstituted 2-amino-4-pyrimidinols as illustrated in Scheme (III),below:

In Scheme (III), R², R⁴, R⁵, R⁶, L¹, L² and X are as previously definedfor Scheme (I) and Z is a leaving group as discussed in more detail inconnection with Scheme IV, infra. Referring to Scheme (III),2-amino-4-pyrimidinol 30 is reacted with amine 6 (or optionallyprotected amine 21) to yield N2-substituted-4-pyrimidinol 32, which isthen halogenated as previously described to yieldN2-substituted-4-halo-2-pyrimidineamine 34. Optional deprotection (forexample if protected amine 21 was used in the first step) followed byreaction with amine 10 affords a 2,4-pyrimidinediamine according tostructural formula (I). Alternatively, pyrimidinol 30 can be reactedwith acylating agent 31.

Suitable commercially-available 2-amino-4-pyrimidinols 30 that can beused as starting materials in Scheme (III) include, but are not limitedto, 2-amino-6-chloro-4-pyrimidinol hydrate (Aldrich #A4702-8; CASRegistry 00000-00-0) and 2-amino-6-hydroxy-4-pyrimidinol (Aldrich#A5040-1; CAS Registry 56-09-7). Other 2-amino-4-pyrimidinols 30 usefulas starting materials in Scheme (III) are available from GeneralIntermediates of Canada, Inc., Edmonton, Alberta, Calif.(www.generalintermediates.com) and/or Interchim, France(www.interchim.com), or may be prepared using standard techniques.Myriad textbook references teaching suitable synthetic methods areprovided infra.

Alternatively, the 2,4-pyrimidinediamine compounds of the invention maybe prepared from substituted or unsubstituted 4-amino-2-pyrimidinols asillustrated in Scheme (IV), below:

In Scheme (IV), R², R⁴, R⁵, R⁶, L¹ and L² are as previously defined forScheme (I) and Z represents a leaving group. Referring to Scheme (IV),the C2-hydroxyl of 4-amino-2-pyrimidinol 40 is more reactive towardsnucleophiles than the C4-amino such that reaction with amine 6 yieldsN2-substituted-2,4-pyrimidinediamine 42. Subsequent reaction withcompound 44, which includes a good leaving group Z, or amine 10 yields a2,4-pyrimidinediamine according to structural formula (I). Compound 44may include virtually any leaving group that can be displaced by theC4-amino of N2-substituted-2,4-pyrimidinediamine 42. Suitable leavinggroups Z include, but are not limited to, halogens, methanesulfonyloxy(mesyloxy; “OMs”), trifluoromethanesulfonyloxy (“OTf”) andp-toluenesulfonyloxy (tosyloxy; “OTs”), benzene sulfonyloxy (“besylate”)and metanitro benzene sulfonyloxy (“nosylate”). Other suitable leavinggroups will be apparent to those of skill in the art.

Substituted 4-amino-2-pyrimidinol starting materials may be obtainedcommercially or synthesized using standard techniques. Myriad textbookreferences teaching suitable synthetic methods are provided infra.

In still another exemplary embodiment, the 2,4-pyrimidinediaminecompounds of the invention can be prepared from2-chloro-4-aminopyrimidines or 2-amino-4-chloropyrimidines asillustrated in Scheme (V), below:

In Scheme (V), R², R⁴, R⁵, R⁶, L¹, L² and X are as defined for Scheme(I) and Z is as defined for Scheme (IV). Referring to Scheme (V),2-amino-4-chloropyrimidine 50 is reacted with amino 10 to yield4N-substituted-2-pyrimidineamine 52 which, following reaction withcompound 31 or amine 6, yields a 2,4-pyrimidinediamine according tostructural formula (I). Alternatively, 2-chloro-4-amino-pyrimidine 54may be reacted with compound 44 followed by amine 6 to yield a compoundaccording to structural formula (I).

A variety of pyrimidines 50 and 54 suitable for use as startingmaterials in Scheme (V) are commercially available, including by way ofexample and not limitation, 2-amino-4,6-dichloropyrimidine (Aldrich#A4860-1; CAS Registry 56-05-3); 2-amino-4-chloro-6-methoxy-pyrimidine(Aldrich #51,864-6; CAS Registry 5734-64-5);2-amino-4-chloro-6-methylpyrimidine (Aldrich #12,288-2; CAS Registry5600-21-5); and 2-amino-4-chloro-6-methylthiopyrimidine (Aldrich#A4600-5; CAS Registry 1005-38-5). Additional pyrimidine startingmaterials are available from General Intermediates of Canada, Inc.,Edmonton, Alberta, Calif. (www.generalintermediates.com) and/orInterchim, France (www.interchim.com), or may be prepared using standardtechniques. Myriad textbook references teaching suitable syntheticmethods are provided infra.

Alternatively, 4-chloro-2-pyrimidineamines 50 may be prepared asillustrated in Scheme (Va):

In Scheme (Va), R⁵ and R⁶ are as previously defined for structuralformula (I). In Scheme (Va), dicarbonyl 53 is reacted with guanidine toyield 2-pyrimidineamine 51. Reaction with peracids likem-chloroperbenzoic acid, trifluoroperacetic acid or urea hydrogenperoxide complex yields N-oxide 55, which is then halogenated to give4-chloro-2-pyrimidineamine 50. The corresponding4-halo-2-pyrimidineamines may be obtained by using suitable halogenationreagents.

In yet another exemplary embodiment, the 2,4-pyrimidinediamine compoundsof the invention can be prepared from substituted or unsubstituteduridines as illustrated in Scheme (VI), below:

In Scheme (VI), R², R⁴, R⁵, R⁶, L¹, L² and X are as previously definedfor Scheme (I) and the superscript PG represents a protecting group, asdiscussed in connection with Scheme (IIb). According to Scheme (VI),uridine 60 has a C4 reactive center such that reaction with amine 10 orprotected amine 21 yields N4-substituted cytidine 62 or 64,respectively. Acid-catalyzed deprotection of N4-substituted 62 or 64(when “PG” represents an acid-labile protecting group) yieldsN4-substituted cytosine 28, which may be subsequently halogenated at theC2-position and reacted with amine 6 to yield a 2,4-pyrimidinediamineaccording to structural formula (I).

Cytidines may also be used as starting materials in an analogous manner,as illustrated in Scheme (VII), below:

In Scheme (VII), R², R⁴, R⁵, R⁶, L¹, L² and X are as previously definedin Scheme (I) and the superscript PG represents a protecting group asdiscussed above. Referring to Scheme (VII), like uridine 60, cytidine 70has a C4 reactive center such that reaction with amine 10 or protectedamine 21 yields N4-substituted cytidine 62 or 64, respectively. Thesecytidines 62 and 64 are then treated as previously described for Scheme(VI) to yield a 2,4-pyrimidinediamine according to structural formula(I).

Although Schemes (VI) and (VII) are exemplified with ribosylnucleosides,skilled artisans will appreciate that the corresponding 2′-deoxyribo and2′,3′-dideoxyribo nucleosides, as well as nucleosides including sugarsor sugar analogs other than ribose, would also work.

Numerous uridines and cytidines useful as starting materials in Schemes(VI) and (VII) are known in the art, and include, by way of example andnot limitation, 5-trifluoromethyl-2′-deoxycytidine (Chem. Sources #ABCRF07669; CAS Registry 66,384-66-5); 5-bromouridine (Chem. SourcesInt′12000; CAS Registry 957-75-5); 5-iodo-2′-deoxyuridine (Aldrich#1-775-6; CAS Registry 54-42-2); 5-fluorouridine (Aldrich #32,937-1; CASRegistry 316-46-1); 5-iodouridine (Aldrich #85,259-7; CAS Registry1024-99-3); 5-(trifluoromethyl)uridine (Chem. Sources Int'l 2000; CASRegistry 70-00-8); 5-trifluoromethyl-2′-deoxyuridine (Chem. SourcesInt′12000; CAS Registry 70-00-8). Additional uridines and cytidines thatcan be used as starting materials in Schemes (VI) and (VII) areavailable from General Intermediates of Canada, Inc., Edmonton, Alberta,Calif. (www.generalintermediates.com) and/or Interchim, France(www.interchim.com), or may be prepared using standard techniques.Myriad textbook references teaching suitable synthetic methods areprovided infra.

The 2,4-pyrimidinediamine compounds of the invention can also besynthesized from substituted pyrimidines, such as chloro-substitutedpyrimidines, as illustrated in Schemes (VIII) and (IX), below:

In Schemes (VIII) and (IX), R², R⁴, L¹, L² and R^(a) are as previouslydefined for structural formula (I) and “Ar” represents an aryl group.Referring to Scheme (VIII), reaction of 2,4,6-trichloropyrimidine 80(Aldrich #T5,620-0; CAS #3764-01-0) with amine 6 yields a mixture ofthree compounds: substituted pyrimidine mono-, di- and triamines 81, 82and 83, which can be separated and isolated using HPLC or otherconventional techniques. Mono- and diamines 81 and 82 may be furtherreacted with amines 6 and/or 10 to yieldN2,N4,N6-trisubstituted-2,4,6-pyrimidinetriamines 84 and 85,respectively.

N2,N4-bis-substituted-2,4-pyrimidinediamines can be prepared in a manneranalogous to Scheme (VIII) by employing 2,4-dichloro-5-methylpyrimidineor 2,4-dichloro-pyrimidine as starting materials. In this instance, themono-substituted pyrimidineamine corresponding to compound 81 is notobtained. Instead, the reaction proceeds to yield theN2,N4-bis-substituted-2,4-pyrimidinediamine directly.

Referring to Scheme (IX), 2,4,5,6-tetrachloropyrimidine 90 (Aldrich#24,671-9; CAS #1780-40-1) is reacted with excess amine 6 to yield amixture of three compounds: 91, 92, and 93, which can be separated andisolated using HPLC or other conventional techniques. As illustrated,N2,N4-bis-substituted-5,6,-dichloro-2,4-pyrimidinediamine 92 may befurther reacted at the C6 halide with, for example a nucleophilic agent94 to yield compound 95. Alternatively, compound 92 can be convertedinto N2,N4-bis-substituted-5-chloro-6-aryl-2,4-pyrimidinediamine 97 viaa Suzuki reaction. 2,4-Pyrimidinediamine 95 may be converted to2,4-pyrimidinediamine 99 by reaction with Bn3SnH.

As will be recognized by skilled artisans, 2,4-pyrimidinediaminesaccording to the invention, synthesized via the exemplary methodsdescribed above or by other well-known means, may also be utilized asstarting materials and/or intermediates to synthesize additional2,4-pyrimidinediamine compounds of the invention. A specific example isillustrated in Scheme (X), below:

In Scheme (X), R⁴, R⁵, R⁶, L² and R^(a) are as previously defined forstructural formula (I). Each R^(a′) is independently an R^(a), and maybe the same or different from the illustrated R^(a). Referring to Scheme(X), carboxylic acid or ester 100 may be converted to amide 104 byreaction with amine 102. In amine 102, R^(a′) may be the same ordifferent than R^(a) of acid or ester 100. Similarly, carbonate ester106 may be converted to carbamate 108.

A second specific example is illustrated in Scheme (XI), below:

In Scheme (XI), R⁴, R⁵, R⁶, L² and R^(c) are as previously defined forstructural formula (I). Referring to Scheme (XI), amide 110 or 116 maybe converted to amine 114 or 118, respectively, by borane reduction withborane methylsulfide complex 112. Other suitable reactions forsynthesizing 2,4-pyrimidinediamine compounds from 2,4-pyrimidinediaminestarting materials will be apparent to those of skill in the art.

Although many of the synthetic schemes discussed above do not illustratethe use of protecting groups, skilled artisans will recognize that insome instances substituents R², R⁴, R⁵, R⁶, L¹ and/or L² may includefunctional groups requiring protection. The exact identity of theprotecting group used will depend upon, among other things, the identityof the functional group being protected and the reaction conditions usedin the particular synthetic scheme, and will be apparent to those ofskill in the art. Guidance for selecting protecting groups andchemistries for their attachment and removal suitable for a particularapplication can be found, for example, in Greene & Wuts, supra.

Prodrugs according to structural formula (II) may be prepared by routinemodification of the above-described methods. Alternatively, suchprodrugs may be prepared by reacting a suitably protected2,4-pyrimidinediamine of structural formula (I) with a suitableprogroup. Conditions for carrying out such reactions and fordeprotecting the product to yield a prodrug of formula (II) arewell-known.

Myriad references teaching methods useful for synthesizing pyrimidinesgenerally, as well as starting materials described in Schemes (I)-(IX),are known in the art. For specific guidance, the reader is referred toBrown, D. J., “The Pyrimidines”, in The Chemistry of HeterocyclicCompounds, Volume 16 (Weissberger, A., Ed.), 1962, IntersciencePublishers, (A Division of John Wiley & Sons), New York (“Brown I”);Brown, D. J., “The Pyrimidines”, in The Chemistry of HeterocyclicCompounds, Volume 16, Supplement I (Weissberger, A. and Taylor, E. C.,Ed.), 1970, Wiley-Interscience, (A Division of John Wiley & Sons), NewYork (Brown II″); Brown, D. J., “The Pyrimidines”, in The Chemistry ofHeterocyclic Compounds, Volume 16, Supplement II (Weissberger, A. andTaylor, E. C., Ed.), 1985, An Interscience Publication (John Wiley &Sons), New York (“Brown III”); Brown, D. J., “The Pyrimidines” in TheChemistry of Heterocyclic Compounds, Volume 52 (Weissberger, A. andTaylor, E. C., Ed.), 1994, John Wiley & Sons, Inc., New York, pp. 1-1509(Brown IV″); Kenner, G. W. and Todd, A., in Heterocyclic Compounds,Volume 6, (Elderfield, R. C., Ed.), 1957, John Wiley, New York, Chapter7 (pyrimidines); Paquette, L. A., Principles of Modern HeterocyclicChemistry, 1968, W. A. Benjamin, Inc., New York, pp. 1-401 (uracilsynthesis pp. 313, 315; pyrimidine synthesis pp. 313-316; aminopyrimidine synthesis pp. 315); Joule, J. A., Mills, K. and Smith, G. F.,Heterocyclic Chemistry, 3^(rd) Edition, 1995, Chapman and Hall, London,UK, pp. 1-516; Vorbrüggen, H. and Ruh-Pohlenz, C., Handbook ofNucleoside Synthesis, John Wiley & Sons, New York, 2001, pp. 1-631(protection of pyrimidines by acylation pp. 90-91; silylation ofpyrimidines pp. 91-93); Joule, J. A., Mills, K. and Smith, G. F.,Heterocyclic Chemistry, 4^(th) Edition, 2000, Blackwell Science, Ltd,Oxford, UK, pp. 1-589; and Comprehensive Organic Synthesis, Volumes 1-9(Trost, B. M. and Fleming, I., Ed.), 1991, Pergamon Press, Oxford, UK.

It should be understood by the skilled artisan that in Schemes I throughXI, the N4 nitrogen can be substituted by R^(4c) as described throughoutthe specification and in the examples provided herein.

6.4 Inhibition of Fc Receptor Signal Cascades

Active 2,4-pyrimidinediamine compounds of the invention inhibit Fcreceptor signalling cascades that lead to, among other things,degranulation of cells. As a specific example, the compounds inhibit theFcεRI and/or FcγRI signal cascades that lead to degranulation of immunecells such as neutrophil, eosinophil, mast and/or basophil cells. Bothmast and basophil cells play a central role in allergen-induceddisorders, including, for example, allergic rhinitis and asthma.Referring to FIG. 1, upon exposure allergens, which may be, among otherthings, pollen or parasites, allergen-specific IgE antibodies aresynthesized by B-cells activated by IL-4 (or IL-13) and other messengersto switch to IgE class specific antibody synthesis. Theseallergen-specific IgEs bind to the high affinity FcεRI. Upon binding ofantigen, the FcεR1-bound IgEs are cross-linked and the IgE receptorsignal transduction pathway is activated, which leads to degranulationof the cells and consequent release and/or synthesis of a host ofchemical mediators, including histamine, proteases (e.g., tryptase andchymase), lipid mediators such as leukotrienes (e.g., LTC4),platelet-activating factor (PAF) and prostaglandins (e.g., PGD2) and aseries of cytokines, including TNF-α, IL-4, IL-13, IL-5, IL-6, IL-8,GMCSF, VEGF and TGF-β. The release and/or synthesis of these mediatorsfrom mast and/or basophil cells accounts for the early and late stageresponses induced by allergens, and is directly linked to downstreamevents that lead to a sustained inflammatory state.

The molecular events in the FcεRI signal transduction pathway that leadto release of preformed mediators via degranulation and release and/orsynthesis of other chemical mediators are well-known and are illustratedin FIG. 2. Referring to FIG. 2, the FcεRI is a heterotetrameric receptorcomposed of an IgE-binding alpha-subunit, a beta subunit, and two gammasubunits (gamma homodimer). Cross-linking of FcεRI-bound IgE bymultivalent binding agents (including, for example IgE-specificallergens or anti-IgE antibodies or fragments) induces the rapidassociation and activation of the Src-related kinase Lyn. Lynphosphorylates immunoreceptor tyrosine-based activation motifs (ITAMS)on the intracellular beta and gamma subunits, which leads to therecruitment of additional Lyn to the beta subunit and Syk kinase to thegamma homodimer. These receptor-associated kinases, which are activatedby intra- and intermolecular phosphorylation, phosphorylate othercomponents of the pathway, such as the Btk kinase, LAT, andphospholipase C-gamma PLC-gamma). Activated PLC-gamma initiates pathwaysthat lead to protein kinase C activation and Ca²⁺ mobilization, both ofwhich are required for degranulation. FcεR1 cross-linking also activatesthe three major classes of mitogen activated protein (MAP) kinases, i.e.ERK1/2, JNK1/2, and p38. Activation of these pathways is important inthe transcriptional regulation of proinflammatory mediators, such asTNF-α and IL-6, as well as the lipid mediator leukotriene CA (LTC4).

Although not illustrated, the FcγRI signaling cascade is believed toshare some common elements with the FceRI signaling cascade.Importantly, like FcεRI, the FcγRI includes a gamma homodimer that isphosphorylated and recruits Syk, and like FcεRI, activation of the FcγRIsignaling cascade leads to, among other things, degranulation. Other Fcreceptors that share the gamma homodimer, and which can be regulated bythe active 2,4-pyrimidinediamine compounds include, but are not limitedto, FcαRI and FcγRIII

The ability of the 2,4-pyrimidinediamine compounds of the invention toinhibit Fc receptor signaling cascades may be simply determined orconfirmed in in vitro assays. Suitable assays for confirming inhibitionof FcεRI-mediated degranulation are provided in the Examples section. Inone typical assay, cells capable of undergoing FcεRI-mediateddegranulation, such as mast or basophil cells, are first grown in thepresence of IL-4, Stem Cell Factor (SCF), IL-6 and IgE to increaseexpression of the FcεRI, exposed to a 2,4-pyrimidinediamine testcompound of the invention and stimulated with anti-IgE antibodies (or,alternatively, an IgE-specific allergen). Following incubation, theamount of a chemical mediator or other chemical agent released and/orsynthesized as a consequence of activating the FcεRI signaling cascademay be quantified using standard techniques and compared to the amountof the mediator or agent released from control cells (i.e., cells thatare stimulated but that are not exposed to test compound). Theconcentration of test compound that yields a 50% reduction in thequantity of the mediator or agent measured as compared to control cellsis the IC50 of the test compound. The origin of the mast or basophilcells used in the assay will depend, in part, on the desired use for thecompounds and will be apparent to those of skill in the art. Forexample, if the compounds will be used to treat or prevent a particulardisease in humans, a convenient source of mast or basophil cells is ahuman or other animal which constitutes an accepted or known clinicalmodel for the particular disease. Thus, depending upon the particularapplication, the mast or basophil cells may be derived from a widevariety of animal sources, ranging from, for example, lower mammals suchas mice and rats, to dogs, sheep and other mammals commonly employed inclinical testing, to higher mammals such as monkeys, chimpanzees andapes, to humans. Specific examples of cells suitable for carrying outthe in vitro assays include, but are not limited to, rodent or humanbasophil cells, rat basophil leukemia cell lines, primary mouse mastcells (such as bone marrow-derived mouse mast cells “BMMC”) and primaryhuman mast cells isolated from cord blood (“CHMC”) or other tissues suchas lung. Methods for isolating and culturing these cell types arewell-known or are provided in the Examples section (see, e.g., Demo etal., 1999, Cytometry 36(4):340-348 and copending application Ser. No.10/053,355, filed Nov. 8, 2001, the disclosures of which areincorporated herein by reference). Of course, other types of immunecells that degranulate upon activation of the FcεRI signaling cascademay also be used, including, for example, eosinophils.

As will be recognized by skilled artisans, the mediator or agentquantified is not critical. The only requirement is that it be amediator or agent released and/or synthesized as a consequence ofinitiating or activating the Fc receptor signaling cascade. For example,referring to FIG. 1, activation of the FcεRI signaling cascade in mastand/or basophil cells leads to numerous downstream events. For example,activation of the FcεRI signal cascade leads to the immediate release(i.e., within 1-3 min. following receptor activation) of a variety ofpreformed chemical mediators and agents via degranulation. Thus, in oneembodiment, the mediator or agent quantified may be specific to granules(i.e., present in granules but not in the cell cytoplasm generally).Examples of granule-specific mediators or agents that can be quantifiedto determine and/or confirm the activity of a 2,4-pyrimidinediaminecompound of the invention include, but are not limited to,granule-specific enzymes such as hexosaminidase and tryptase andgranule-specific components such as histamine and serotonin. Assays forquantifying such factors are well-known, and in many instances arecommercially available. For example, tryptase and/or hexosaminidaserelease may be quantified by incubating the cells with cleavablesubstrates that fluoresce upon cleavage and quantifying the amount offluorescence produced using conventional techniques. Such cleavablefluorogenic substrates are commercially available. For example, thefluorogenic substrates Z-Gly-Pro-Arg-AMC (Z=benzyloxycarbonyl;AMC=7-amino-4-methylcoumarin; BIOMOL Research Laboratories, Inc.,Plymouth Meeting, Pa. 19462, Catalog No. P-142) and Z-Ala-Lys-Arg-AMC(Enzyme Systems Products, a division of ICN Biomedicals, Inc.,Livermore, Calif. 94550, Catalog No. AMC-246) can be used to quantifythe amount of tryptase released. The fluorogenic substrate4-methylumbelliferyl-N-acetyl-β-D-glucosaminide (Sigma, St. Louis, Mo.,Catalog #69585) can be used to quantify the amount of hexosaminidasereleased. Histamine release may be quantified using a commerciallyavailable enzyme-linked immunosorbent assay (ELISA) such as Immunotechhistamine ELISA assay #IM2015 (Beckman-Coulter, Inc.). Specific methodsof quantifying the release of tryptase, hexosaminidase and histamine areprovided in the Examples section. Any of these assays may be used todetermine or confirm the activity of the 2,4-pyrimidinediamine compoundsof the invention.

Referring again to FIG. 1, degranulation is only one of severalresponses initiated by the FcεRI signaling cascade. In addition,activation of this signaling pathway leads to the de novo synthesis andrelease of cytokines and chemokines such as IL-4, IL-5, IL-6, TNF-α,IL-13 and MIP1-α), and release of lipid mediators such as leukotrienes(e.g., LTC4), platelet activating factor (PAF) and prostaglandins.Accordingly, the 2,4-pyrimidinediamine compounds of the invention mayalso be assessed for activity by quantifying the amount of one or moreof these mediators released and/or synthesized by activated cells.

Unlike the granule-specific components discussed above, these “latestage” mediators are not released immediately following activation ofthe FcεRI signaling cascade. Accordingly, when quantifying these latestage mediators, care should be taken to insure that the activated cellculture is incubated for a time sufficient to result in the synthesis(if necessary) and release of the mediator being quantified. Generally,PAF and lipid mediators such as leukotriene C4 are released 3-30 min.following FcεRI activation. The cytokines and other late stage mediatorsare released approx. 4-8 hrs. following FcεRI activation. Incubationtimes suitable for a specific mediator will be apparent to those ofskill in the art. Specific guidance and assays are provided in theExamples section.

The amount of a particular late stage mediator released may bequantified using any standard technique. In one embodiment, theamount(s) may be quantified using ELISA assays. ELISA assay kitssuitable for quantifying the amount of TNFα, IL-4, IL-5, IL-6 and/orIL-13 released are available from, for example, Biosource International,Inc., Camarillo, Calif. 93012 (see, e.g., Catalog Nos. KHC3011, KHC0042,KHC0052, KHC0061 and KHC0132). ELISA assay kits suitable for quantifyingthe amount of leukotriene C4 (LTC4) released from cells are availablefrom Cayman Chemical Co., Ann Arbor, Mich. 48108 (see, e.g., Catalog No.520211).

Typically, active 2,4-pyrimidinediamine compounds of the invention willexhibit IC₅₀s with respect to FcεRI-mediated degranulation and/ormediator release or synthesis of about 20 μM or lower, as measured in anin vitro assay, such as one of the in vitro assays described above or inthe Examples section. Of course, skilled artisans will appreciate thatcompounds which exhibit lower IC₅₀s, for example on the order of 10 μM,1 μM, 100 nM, 10 nM, 1 nM, or even lower, are particularly useful.

Skilled artisans will also appreciate that the various mediatorsdiscussed above may induce different adverse effects or exhibitdifferent potencies with respect to the same adverse effect. Forexample, the lipid mediator LTC4 is a potent vasoconstrictor—it isapproximately 1000-fold more potent at inducing vasoconstriction thanhistamine. As another example, in addition to mediating atopic or Type Ihypersensitivity reactions, cytokines can also cause tissue remodelingand cell proliferation. Thus, although compounds that inhibit releaseand/or synthesis of any one of the previously discussed chemicalmediators are useful, skilled artisans will appreciate that compoundswhich inhibit the release and/or synthesis of a plurality, or even all,of the previously described mediators find particular use, as suchcompounds are useful for ameliorating or avoiding altogether aplurality, or even all, of the adverse effects induced by the particularmediators. For example, compounds which inhibit the release of all threetypes of mediators—granule-specific, lipid and cytokine—are useful fortreating or preventing immediate Type I hypersensitivity reactions aswell as the chronic symptoms associated therewith.

Compounds of the invention capable of inhibiting the release of morethan one type of mediator (e.g., granule-specific or late stage) may beidentified by determining the IC50 with respect to a mediatorrepresentative of each class using the various in vitro assays describedabove (or other equivalent in vitro assays). Compounds of the inventionwhich are capable of inhibiting the release of more than one mediatortype will typically exhibit an IC₅₀ for each mediator type tested ofless than about 20 μM. For example, a compound which exhibits an IC₅₀ of1 μM with respect to histamine release (IC₅₀ ^(histamine)) and an IC₅₀of 1 nM with respect to leukotriene LTC4 synthesis and/or release (IC₅₀^(LTC4)) inhibits both immediate (granule-specific) and late stagemediator release. As another specific example, a compound that exhibitsan IC₅₀ ^(tryptase) of 10 μM, an IC₅₀ ^(LTC4) of 1 μM and an IC₅₀^(IL-4) of 1 μM inhibits immediate (granule-specific), lipid andcytokine mediator release. Although the above specific examples utilizethe IC₅₀s of one representative mediator of each class, skilled artisanswill appreciate that the IC₅₀s of a plurality, or even all, mediatorscomprising one or more of the classes may be obtained. The quantity(ies)and identity(ies) of mediators for which IC₅₀ data should be ascertainedfor a particular compound and application will be apparent to those ofskill in the art.

Similar assays may be utilized to confirm inhibition of signaltransduction cascades initiated by other Fc receptors, such as FcαRI,FcγRI and/or FcγRIII signaling, with routine modification. For example,the ability of the compounds to inhibit FcγRI signal transduction may beconfirmed in assays similar to those described above, with the exceptionthat the FcγRI signaling cascade is activated, for example by incubatingthe cells with IgG and an IgG-specific allergen or antibody, instead ofIgE and an IgE-specific allergen or antibody. Suitable cell types,activating agents and agents to quantify to confirm inhibition of otherFc receptors, such as Fc receptors that comprise a gamma homodimer, willbe apparent to those of skill in the art.

One particularly useful class of compounds includes those2,4-pyrimidinediamine compounds that inhibit the release of immediategranule-specific mediators and late stage mediators with approximatelyequivalent IC₅₀s. By approximately equivalent is meant that the IC₅₀sfor each mediator type are within about a 10-fold range of one another.Another particularly useful class of compounds includes those2,4-pyrimidinediamine compounds that inhibit the release of immediategranule-specific mediators, lipid mediators and cytokine mediators withapproximately equivalent IC₅₀s. In a specific embodiment, such compoundsinhibit the release of the following mediators with approximatelyequivalent IC₅₀s: histamine, tryptase, hexosaminidase, IL-4, IL-5, IL-6,IL-13, TNFα and LTC4. Such compounds are particularly useful for, amongother things, ameliorating or avoiding altogether both the early andlate stage responses associated with atopic or immediate Type Ihypersensitivity reactions.

Ideally, the ability to inhibit the release of all desired types ofmediators will reside in a single compound. However, mixtures ofcompounds can also be identified that achieve the same result. Forexample, a first compound which inhibits the release of granule specificmediators may be used in combination with a second compound whichinhibits the release and/or synthesis of cytokine mediators.

In addition to the FcεRI or FcγRI degranulation pathways discussedabove, degranulation of mast and/or basophil cells can be induced byother agents. For example, ionomycin, a calcium ionophore that bypassesthe early FcεRI or FcγRI signal transduction machinery of the cell,directly induces a calcium flux that triggers degranulation. Referringagain to FIG. 2, activated PLCγ initiates pathways that lead to, amongother things, calcium ion mobilization and subsequent degranulation. Asillustrated, this Ca²⁺ mobilization is triggered late in the FcεRIsignal transduction pathway. As mentioned above, and as illustrated inFIG. 3, ionomycin directly induces Ca²⁺ mobilization and a Ca²⁺ fluxthat leads to degranulation.

Other ionophores that induce degranulation in this manner includeA23187. The ability of granulation-inducing ionophores such as ionomycinto bypass the early stages of the FcεRI and/or FcγRI signaling cascadesmay be used as a counter screen to identify active compounds of theinvention that specifically exert their degranulation-inhibitoryactivity by blocking or inhibiting the early FcεRI or FcγRI signalingcascades, as discussed above. Compounds which specifically inhibit suchearly FcεRI or FcγRI-mediated degranulation inhibit not onlydegranulation and subsequent rapid release of histamine, tryptase andother granule contents, but also inhibit the pro-inflammatory activationpathways causing the release of TNFα, IL-4, IL-13 and the lipidmediators such as LTC4. Thus, compounds which specifically inhibit suchearly FcεRI and/or FcγRI-mediated degranulation block or inhibit notonly acute atopic or Type I hypersensitivity reactions, but also lateresponses involving multiple inflammatory mediators.

Compounds of the invention that specifically inhibit early FcεRI and/orFcγRI-mediated degranulation are those compounds that inhibit FcεRIand/or FcγRI-mediated degranulation (for example, have an IC₅₀ of lessthan about 20 μM with respect to the release of a granule-specificmediator or component as measured in an in vitro assay with cellsstimulated with an IgE or IgG binding agent) but that do not appreciablyinhibit ionophore-induced degranulation. In one embodiment, compoundsare considered to not appreciably inhibit ionophore-induceddegranulation if they exhibit an IC₅₀ of ionophore-induced degranulationof greater than about 20 μM, as measured in an in vitro assay. Ofcourse, active compounds that exhibit even higher IC₅₀s ofionophore-induced degranulation, or that do not inhibitionophore-induced degranulation at all, are particularly useful. Inanother embodiment, compounds are considered to not appreciably inhibitionophore-induced degranulation if they exhibit a greater than 10-folddifference in their IC₅₀s of FcεRI and/or FcγRI-mediated degranulationand ionophore-induced degranulation, as measured in an in vitro assay.Assays suitable for determining the IC₅₀ of ionophore-induceddegranulation include any of the previously-described degranulationassays, with the modification that the cells are stimulated or activatedwith a degranulation-inducing calcium ionophore such as ionomycin orA23187 (A.G. Scientific, San Diego, Calif.) instead of anti-IgEantibodies or an IgE-specific allergen. Specific assays for assessingthe ability of a particular 2,4-pyrimidinediamine compound of theinvention to inhibit ionophore-induced degranulation are provided in theExamples section.

As will be recognized by skilled artisans, compounds which exhibit ahigh degree of selectivity of FcεRI-mediated degranulation findparticular use, as such compounds selectively target the FcεRI cascadeand do not interfere with other degranulation mechanisms. Similarly,compounds which exhibit a high degree of selectivity of FcγRI-mediateddegranulation find particular use, as such compounds selectively targetthe FcγRI cascade and do not interfere with other degranulationmechanisms. Compounds which exhibit a high degree of selectivity aregenerally 10-fold or more selective for FcεRI- or FcγRI-mediateddegranulation over ionophore-induced degranulation, such asionomycin-induced degranulation.

Accordingly, the activity of the 2,4-pyrimidinediamine compounds of theinvention may also be confirmed in biochemical or cellular assays of Sykkinase activity. Referring again to FIG. 2, in the FcεRI signalingcascade in mast and/or basophil cells, Syk kinase phosphorylates LAT andPLC-gamma1, which leads to, among other things, degranulation. Any ofthese activities may be used to confirm the activity of the2,4-pyrimidinediamine compounds of the invention. In one embodiment, theactivity is confirmed by contacting an isolated Syk kinase, or an activefragment thereof with a 2,4-pyrimidinediamine compound in the presenceof a Syk kinase substrate (e.g., a synthetic peptide or a protein thatis known to be phophorylated by Syk in a signaling cascade) andassessing whether the Syk kinase phosphorylated the substrate.Alternatively, the assay may be carried out with cells that express aSyk kinase. The cells may express the Syk kinase endogenously or theymay be engineered to express a recombinant Syk kinase. The cells mayoptionally also express the Syk kinase substrate. Cells suitable forperforming such confirmation assays, as well as methods of engineeringsuitable cells will be apparent to those of skill in the art. Specificexamples of biochemical and cellular assays suitable for confirming theactivity of the 2,4-pyrimidinediamine compounds are provided in theExamples section.

Generally, compounds that are Syk kinase inhibitors will exhibit an IC50with respect to a Syk kinase activity, such as the ability of Syk kinaseto phosphorylate a synthetic or endogenous substrate, in an in vitro orcellular assay in the range of about 20 μM or less. Skilled artisanswill appreciate that compounds that exhibit lower IC50s, such as in therange of 10 μM, 1 μM, 100 nM, 10 nM, 1 nM, or even lower, areparticularly useful.

6.5 Uses and Compositions

As previously discussed, the active compounds of the invention inhibitFc receptor signaling cascades, especially those Fc receptors includinga gamma homodimer, such as the FcεRI and/or FcγRI signaling cascades,that lead to, among other things, the release and/or synthesis ofchemical mediators from cells, either via degranulation or otherprocesses. As also discussed, the active compounds are also potentinhibitors of Syk kinase. As a consequence of these activities, theactive compounds of the invention may be used in a variety of in vitro,in vivo and ex vivo contexts to regulate or inhibit Syk kinase,signaling cascades in which Syk kinase plays a role, Fc receptorsignaling cascades, and the biological responses effected by suchsignaling cascades. For example, in one embodiment, the compounds may beused to inhibit Syk kinase, either in vitro or in vivo, in virtually anycell type expressing Syk kinase. They may also be used to regulatesignal transduction cascades in which Syk kinase plays a role. SuchSyk-dependent signal transduction cascades include, but are not limitedto, the FcεRI, FcγRI, FcγRIII, BCR and integrin signal transductioncascades. The compounds may also be used in vitro or in vivo toregulate, and in particular inhibit, cellular or biological responseseffected by such Syk-dependent signal transduction cascades. Suchcellular or biological responses include, but are not limited to,respiratory burst, cellular adhesion, cellular degranulation, cellspreading, cell migration, cell aggregation, phagcytosis, cytokinesynthesis and release, cell maturation and Ca²⁺ flux. Importantly, thecompounds may be used to inhibit Syk kinase in vivo as a therapeuticapproach towards the treatment or prevention of diseases mediated,either wholly or in part, by a Syk kinase activity. Non-limitingexamples of Syk kinase mediated diseases that may be treated orprevented with the compounds are those discussed in more detail, below.

In another embodiment, the active compounds may be used to regulate orinhibit the Fc receptor signaling cascades and/or FcεRI- and/orFcγRI-mediated degranulation as a therapeutic approach towards thetreatment or prevention of diseases characterized by, caused by and/orassociated with the release or synthesis of chemical mediators of suchFc receptor signaling cascades or degranulation. Such treatments may beadministered to animals in veterinary contexts or to humans. Diseasesthat are characterized by, caused by or associated with such mediatorrelease, synthesis or degranulation, and that can therefore be treatedor prevented with the active compounds include, by way of example andnot limitation, atopy or anaphylactic hypersensitivity or allergicreactions, allergies (e.g., allergic conjunctivitis, allergic rhinitis,atopic asthma, atopic dermatitis and food allergies), low grade scarring(e.g., of scleroderma, increased fibrosis, keloids, post-surgical scars,pulmonary fibrosis, vascular spasms, migraine, reperfusion injury andpost myocardial infarction), diseases associated with tissue destruction(e.g., of COPD, cardiobronchitis and post myocardial infarction),diseases associated with tissue inflammation (e.g., irritable bowelsyndrome, spastic colon and inflammatory bowel disease), inflammationand scarring.

In addition to the myriad diseases discussed above, cellular and animalempirical data confirm that the 2,4-pyrimidinediamine compoundsdescribed herein are also useful for the treatment or prevention ofautoimmune diseases, as well as the various symptoms associated withsuch diseases. The types of autoimmune diseases that may be treated orprevented with the 2,4-pyrimidinediamine compounds generally includethose disorders involving tissue injury that occurs as a result of ahumoral and/or cell-mediated response to immunogens or antigens ofendogenous and/or exogenous origin. Such diseases are frequentlyreferred to as diseases involving the nonanaphylactic (i.e., Type II,Type III and/or Type IV) hypersensitivity reactions.

As discussed previously, Type I hypersensitivity reactions generallyresult from the release of pharmacologically active substances, such ashistamine, from mast and/or basophil cells following contact with aspecific exogenous antigen. As mentioned above, such Type I reactionsplay a role in numerous diseases, including allergic asthma, allergicrhinitis, etc.

Type II hypersensitivity reactions (also referred to as cytotoxic,cytolytic complement-dependent or cell-stimulating hypersensitivityreactions) result when immunoglobulins react with antigenic componentsof cells or tissue, or with an antigen or hapten that has becomeintimately coupled to cells or tissue. Diseases that are commonlyassociated with Type II hypersensitivity reactions include, but are notlimited, to autoimmune hemolytic anemia, erythroblastosis fetalis andGoodpasture's disease.

Type III hypersensitivity reactions, (also referred to as toxic complex,soluble complex, or immune complex hypersensitivity reactions) resultfrom the deposition of soluble circulating antigen-immunoglobulincomplexes in vessels or in tissues, with accompanying acute inflammatoryreactions at the site of immune complex deposition. Non-limitingexamples of prototypical Type III reaction diseases include the Arthusreaction, rheumatoid arthritis, serum sickness, systemic lupuserythematosis, certain types of glomerulonephritis, multiple sclerosisand bullous pemphingoid.

Type IV hypersensitivity reactions (frequently called cellular,cell-mediated, delayed, or tuberculin-type hypersensitivity reactions)are caused by sensitized T-lymphocytes which result from contact with aspecific antigen. Non-limiting examples of diseases cited as involvingType IV reactions are contact dermatitis and allograft rejection.

Autoimmune diseases associated with any of the above nonanaphylactichypersensitivity reactions may be treated or prevented with the2,4-pyrimidinediamine compounds of the invention. In particular, themethods may be used to treat or prevent those autoimmune diseasesfrequently characterized as single organ or single cell-type autoimmunedisorders including, but not limited to: Hashimoto's thyroiditis,autoimmune hemolytic anemia, autoimmune atrophic gastritis of perniciousanemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture'sdisease, autoimmune thrombocytopenia, sympathetic ophthalmia, myastheniagravis, Graves' disease, primary biliary cirrhosis, chronic aggressivehepatitis, ulcerative colitis and membranous glomerulopathy, as well asthose autoimmune diseases frequently characterized as involving systemicautoimmune disorder, which include but are not limited to: systemiclupus erythematosis, rheumatoid arthritis, Sjogren's syndrome, Reiter'ssyndrome, polymyositis-dermatomyositis, systemic sclerosis,polyarteritis nodosa, multiple sclerosis and bullous pemphigoid.

It will be appreciated by skilled artisans that many of the above-listedautoimmune diseases are associated with severe symptoms, theamelioration of which provides significant therapeutic benefit even ininstances where the underlying autoimmune disease may not beameliorated. Many of these symptoms, as well as their underlying diseasestates, result as a consequence of activating the FcγR signaling cascadein monocyte cells. As the 2,4-pyrimidinediamine compounds describedherein are potent inhibitors of such FcγR signaling in monocytes andother cells, the methods find use in the treatment and/or prevention ofmyriad adverse symptoms associated with the above-listed autoimmunediseases.

As a specific example, rheumatoid arthritis (RA) typically results inswelling, pain, loss of motion and tenderness of target jointsthroughout the body. RA is characterized by chronically inflamedsynovium that is densely crowded with lymphocytes. The synovialmembrane, which is typically one cell layer thick, becomes intenselycellular and assumes a form similar to lymphoid tissue, includingdentritic cells, T-, B- and NK cells, macrophages and clusters of plasmacells. This process, as well as a plethora of immunopathologicalmechanisms including the formation of antigen-immunoglobulin complexes,eventually result in destruction of the integrity of the joint,resulting in deformity, permanent loss of function and/or bone erosionat or near the joint. The methods may be used to treat or ameliorate anyone, several or all of these symptoms of RA. Thus, in the context of RA,the methods are considered to provide therapeutic benefit (discussedmore generally, infra) when a reduction or amelioration of any of thesymptoms commonly associated with RA is achieved, regardless of whetherthe treatment results in a concomitant treatment of the underlying RAand/or a reduction in the amount of circulating rheumatoid factor(“RF”).

As another specific example, systemic lupus erythematosis (“SLE”) istypically associated with symptoms such as fever, joint pain(arthralgias), arthritis, and serositis (pleurisy or pericarditis). Inthe context of SLE, the methods are considered to provide therapeuticbenefit when a reduction or amelioration of any of the symptoms commonlyassociated with SLE are achieved, regardless of whether the treatmentresults in a concomitant treatment of the underlying SLE.

As another specific example, multiple sclerosis (“MS”) cripples thepatient by disturbing visual acuity; stimulating double vision;disturbing motor functions affecting walking and use of the hands;producing bowel and bladder incontinence; spasticity; and sensorydeficits (touch, pain and temperature sensitivity). In the context ofMS, the methods are considered to provide therapeutic benefit when animprovement or a reduction in the progression of any one or more of thecrippling effects commonly associated with MS is achieved, regardless ofwhether the treatment results in a concomitant treatment of theunderlying MS.

When used to treat or prevent such diseases, the active compounds may beadministered singly, as mixtures of one or more active compounds or inmixture or combination with other agents useful for treating suchdiseases and/or the symptoms associated with such diseases. The activecompounds may also be administered in mixture or in combination withagents useful to treat other disorders or maladies, such as steroids,membrane stablizers, 5LO inhibitors, leukotriene synthesis and receptorinhibitors, inhibitors of IgE isotype switching or IgE synthesis, IgGisotype switching or IgG synthesis, β-agonists, tryptase inhibitors,aspirin, COX inhibitors, methotrexate, anti-TNF drugs, retuxin, PD4inhibitors, p38 inhibitors, PDE4 inhibitors, and antihistamines, to namea few. The active compounds may be administered per se in the form ofprodrugs or as pharmaceutical compositions, comprising an activecompound or prodrug.

Pharmaceutical compositions comprising the active compounds of theinvention (or prodrugs thereof) may be manufactured by means ofconventional mixing, dissolving, granulating, dragee-making levigating,emulsifying, encapsulating, entrapping or lyophilization processes. Thecompositions may be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients or auxiliarieswhich facilitate processing of the active compounds into preparationswhich can be used pharmaceutically.

The active compound or prodrug may be formulated in the pharmaceuticalcompositions per se, or in the form of a hydrate, solvate, N-oxide orpharmaceutically acceptable salt, as previously described. Typically,such salts are more soluble in aqueous solutions than the correspondingfree acids and bases, but salts having lower solubility than thecorresponding free acids and bases may also be formed.

Pharmaceutical compositions of the invention may take a form suitablefor virtually any mode of administration, including, for example,topical, ocular, oral, buccal, systemic, nasal, injection, transdermal,rectal, vaginal, etc., or a form suitable for administration byinhalation or insufflation.

For topical administration, the active compound(s) or prodrug(s) may beformulated as solutions, gels, ointments, creams, suspensions, etc. asare well-known in the art.

Systemic formulations include those designed for administration byinjection, e.g., subcutaneous, intravenous, intramuscular, intrathecalor intraperitoneal injection, as well as those designed for transdermal,transmucosal oral or pulmonary administration.

Useful injectable preparations include sterile suspensions, solutions oremulsions of the active compound(s) in aqueous or oily vehicles. Thecompositions may also contain formulating agents, such as suspending,stabilizing and/or dispersing agent. The formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multidosecontainers, and may contain added preservatives.

Alternatively, the injectable formulation may be provided in powder formfor reconstitution with a suitable vehicle, including but not limited tosterile pyrogen free water, buffer, dextrose solution, etc., before use.To this end, the active compound(s) may be dried by any art-knowntechnique, such as lyophilization, and reconstituted prior to use.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants are knownin the art.

For oral administration, the pharmaceutical compositions may take theform of, for example, lozenges, tablets or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g., lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g., magnesium stearate, talc or silica); disintegrants (e.g., potatostarch or sodium starch glycolate); or wetting agents (e.g., sodiumlauryl sulfate). The tablets may be coated by methods well known in theart with, for example, sugars, films or enteric coatings.

Liquid preparations for oral administration may take the form of, forexample, elixirs, solutions, syrups or suspensions, or they may bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations may be prepared byconventional means with pharmaceutically acceptable additives such assuspending agents (e.g., sorbitol syrup, cellulose derivatives orhydrogenated edible fats); emulsifying agents (e.g., lecithin oracacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethylalcohol, Cremophore™ or fractionated vegetable oils); and preservatives(e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). Thepreparations may also contain buffer salts, preservatives, flavoring,coloring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound or prodrug, as is well known.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For rectal and vaginal routes of administration, the active compound(s)may be formulated as solutions (for retention enemas) suppositories orointments containing conventional suppository bases such as cocoa butteror other glycerides.

For nasal administration or administration by inhalation orinsufflation, the active compound(s) or prodrug(s) can be convenientlydelivered in the form of an aerosol spray from pressurized packs or anebulizer with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or othersuitable gas. In the case of a pressurized aerosol, the dosage unit maybe determined by providing a valve to deliver a metered amount. Capsulesand cartridges for use in an inhaler or insufflator (for examplecapsules and cartridges comprised of gelatin) may be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

A specific example of an aqueous suspension formulation suitable fornasal administration using commercially-available nasal spray devicesincludes the following ingredients: active compound or prodrug (0.5-20mg/ml); benzalkonium chloride (0.1-0.2 mg/mL); polysorbate 80 (TWEEN®80; 0.5-5 mg/ml); carboxymethylcellulose sodium or microcrystallinecellulose (1-15 mg/ml); phenylethanol (1-4 mg/ml); and dextrose (20-50mg/ml). The pH of the final suspension can be adjusted to range fromabout pH5 to pH7, with a pH of about pH 5.5 being typical.

Another specific example of an aqueous suspension suitable foradministration of the compounds via inhalation, and in particular forsuch administration of a compound of the invention, contains 1-20 mg/mLof the compound or prodrug, 0.1-1% (v/v) Polysorbate 80 (TWEEN®80), 50mM citrate and/or 0.9% sodium chloride.

For ocular administration, the active compound(s) or prodrug(s) may beformulated as a solution, emulsion, suspension, etc. suitable foradministration to the eye. A variety of vehicles suitable foradministering compounds to the eye are known in the art. Specificnon-limiting examples are described in U.S. Pat. Nos. 6,261,547;6,197,934; 6,056,950; 5,800,807; 5,776,445; 5,698,219; 5,521,222;5,403,841; 5,077,033; 4,882,150; and 4,738,851.

For prolonged delivery, the active compound(s) or prodrug(s) can beformulated as a depot preparation for administration by implantation orintramuscular injection. The active ingredient may be formulated withsuitable polymeric or hydrophobic materials (e.g., as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly solublederivatives, e.g., as a sparingly soluble salt. Alternatively,transdermal delivery systems manufactured as an adhesive disc or patchwhich slowly releases the active compound(s) for percutaneous absorptionmay be used. To this end, permeation enhancers may be used to facilitatetransdermal penetration of the active compound(s). Suitable transdermalpatches are described in for example, U.S. Pat. No. 5,407,713;5,352,456; 5,332,213; 5,336,168; 5,290,561; 5,254,346; 5,164,189;5,163,899; 5,088,977; 5,087,240; 5,008,110; and 4,921,475.

Alternatively, other pharmaceutical delivery systems may be employed.Liposomes and emulsions are well-known examples of delivery vehiclesthat may be used to deliver active compound(s) or prodrug(s). Certainorganic solvents such as dimethylsulfoxide (DMSO) may also be employed,although usually at the cost of greater toxicity.

The pharmaceutical compositions may, if desired, be presented in a packor dispenser device which may contain one or more unit dosage formscontaining the active compound(s). The pack may, for example, comprisemetal or plastic foil, such as a blister pack. The pack or dispenserdevice may be accompanied by instructions for administration.

6.6 Effective Dosages

The active compound(s) or prodrug(s) of the invention, or compositionsthereof, will generally be used in an amount effective to achieve theintended result, for example in an amount effective to treat or preventthe particular disease being treated. The compound(s) may beadministered therapeutically to achieve therapeutic benefit orprophylactically to achieve prophylactic benefit. By therapeutic benefitis meant eradication or amelioration of the underlying disorder beingtreated and/or eradication or amelioration of one or more of thesymptoms associated with the underlying disorder such that the patientreports an improvement in feeling or condition, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forexample, administration of a compound to a patient suffering from anallergy provides therapeutic benefit not only when the underlyingallergic response is eradicated or ameliorated, but also when thepatient reports a decrease in the severity or duration of the symptomsassociated with the allergy following exposure to the allergen. Asanother example, therapeutic benefit in the context of asthma includesan improvement in respiration following the onset of an asthmaticattack, or a reduction in the frequency or severity of asthmaticepisodes. Therapeutic benefit also includes halting or slowing theprogression of the disease, regardless of whether improvement isrealized.

For prophylactic administration, the compound may be administered to apatient at risk of developing one of the previously described diseases.For example, if it is unknown whether a patient is allergic to aparticular drug, the compound may be administered prior toadministration of the drug to avoid or ameliorate an allergic responseto the drug. Alternatively, prophylactic administration may be appliedto avoid the onset of symptoms in a patient diagnosed with theunderlying disorder. For example, a compound may be administered to anallergy sufferer prior to expected exposure to the allergen. Compoundsmay also be administered prophylactically to healthy individuals who arerepeatedly exposed to agents known to one of the above-describedmaladies to prevent the onset of the disorder. For example, a compoundmay be administered to a healthy individual who is repeatedly exposed toan allergen known to induce allergies, such as latex, in an effort toprevent the individual from developing an allergy. Alternatively, acompound may be administered to a patient suffering from asthma prior topartaking in activities which trigger asthma attacks to lessen theseverity of, or avoid altogether, an asthmatic episode.

The amount of compound administered will depend upon a variety offactors, including, for example, the particular indication beingtreated, the mode of administration, whether the desired benefit isprophylactic or therapeutic, the severity of the indication beingtreated and the age and weight of the patient, the bioavailability ofthe particular active compound, etc. Determination of an effectivedosage is well within the capabilities of those skilled in the art.

Effective dosages may be estimated initially from in vitro assays. Forexample, an initial dosage for use in animals may be formulated toachieve a circulating blood or serum concentration of active compoundthat is at or above an IC₅₀ of the particular compound as measured in asin vitro assay, such as the in vitro CHMC or BMMC and other in vitroassays described in the Examples section. Calculating dosages to achievesuch circulating blood or serum concentrations taking into account thebioavailability of the particular compound is well within thecapabilities of skilled artisans. For guidance, the reader is referredto Fingl & Woodbury, “General Principles,” In: Goodman and Gilman's ThePharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, latestedition, Pagamonon Press, and the references cited therein.

Initial dosages can also be estimated from in vivo data, such as animalmodels. Animal models useful for testing the efficacy of compounds totreat or prevent the various diseases described above are well-known inthe art. Suitable animal models of hypersensitivity or allergicreactions are described in Foster, 1995, Allergy 50(21Supp1):6-9,discussion 34-38 and Tumas et al., 2001, J. Allergy Clin. Immunol.107(6):1025-1033. Suitable animal models of allergic rhinitis aredescribed in Szelenyi et al., 2000, Arzneimittelforschung50(11):1037-42; Kawaguchi et al., 1994, Clin. Exp. Allergy 24(3):238-244and Sugimoto et al., 2000, Immunopharmacology 48(1):1-7. Suitable animalmodels of allergic conjunctivitis are described in Carreras et al.,1993, Br. J. Ophthalmol. 77(8):509-514; Saiga et al., 1992, OphthalmicRes. 24(1):45-50; and Kunert et al., 2001, Invest. Ophthalmol. Vis. Sci.42(11):2483-2489. Suitable animal models of systemic mastocytosis aredescribed in O'Keefe et al., 1987, J. Vet. Intern. Med. 1(2):75-80 andBean-Knudsen et al., 1989, Vet. Pathol. 26(1):90-92. Suitable animalmodels of hyper IgE syndrome are described in Claman et al., 1990, Clin.Immunol. Immunopathol. 56(1):46-53. Suitable animal models of B-celllymphoma are described in Hough et al., 1998, Proc. Natl. Acad. Sci. USA95:13853-13858 and Hakim et al., 1996, J. Immunol. 157(12):5503-5511.Suitable animal models of atopic disorders such as atopic dermatitis,atopic eczema and atopic asthma are described in Chan et al., 2001, J.Invest. Dermatol. 117(4):977-983 and Suto et al., 1999, Int. Arch.Allergy Immunol. 120(Suppl 1):70-75. Ordinarily skilled artisans canroutinely adapt such information to determine dosages suitable for humanadministration. Additional suitable animal models are described in theExamples section.

Dosage amounts will typically be in the range of from about 0.0001 or0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but may be higher orlower, depending upon, among other factors, the activity of thecompound, its bioavailability, the mode of administration and variousfactors discussed above. Dosage amount and interval may be adjustedindividually to provide plasma levels of the compound(s) which aresufficient to maintain therapeutic or prophylactic effect. For example,the compounds may be administered once per week, several times per week(e.g., every other day), once per day or multiple times per day,depending upon, among other things, the mode of administration, thespecific indication being treated and the judgment of the prescribingphysician. In cases of local administration or selective uptake, such aslocal topical administration, the effective local concentration ofactive compound(s) may not be related to plasma concentration. Skilledartisans will be able to optimize effective local dosages without undueexperimentation.

Preferably, the compound(s) will provide therapeutic or prophylacticbenefit without causing substantial toxicity. Toxicity of thecompound(s) may be determined using standard pharmaceutical procedures.The dose ratio between toxic and therapeutic (or prophylactic) effect isthe therapeutic index. Compounds(s) that exhibit high therapeuticindices are preferred.

The invention having been described, the following examples are offeredby way of illustration and not limitation.

7. EXAMPLES

7.1 2,4-Pyrimidinediamine Compounds

A variety of N4-substituted-N2-monosubstituted-4-pyrimidinediamines wereprepared based on procedures described herein. Such compounds aredepicted in Table 1.

7.2 The 2,4-Pyrimidinediamine Compounds of the Invention Inhibit FcεRIReceptor-Mediated Degranulation

The ability of the 2,4-pyrimidinediamine compounds of the invention toinhibit IgE-induced degranulation was demonstrated in a variety ofcellular assays with cultured human mast cells (CHMC) and/or mouse bonemarrow derived cells (BMMC). Inhibition of degranulation was measured atboth low and high cell density by quantifying the release of the granulespecific factors tryptase, histamine and hexosaminidase. Inhibition ofrelease and/or synthesis of lipid mediators was assessed by measuringthe release of leukotriene LTC4 and inhibition of release and/orsynthesis of cytokines was monitored by quantifying TNF-α, IL-6 andIL-13. Tryptase and hexosaminidase were quantified using fluorogenicsubstrates as described in their respective examples. Histamine, TNFα,IL-6, IL-13 and LTC4 were quantified using the following commercialELISA kits: histamine (Immunotech #2015, Beckman Coulter), TNFα(Biosource #KHC3011), IL-6 (Biosource #KMC0061), IL-13 (Biosource#KHC0132) and LTC4 (Cayman Chemical #520211). The protocols of thevarious assays are provided below.

7.2.1 Culturing of Human Mast and Basophil Cells

Human mast and basophil cells were cultured from CD34-negativeprogenitor cells as described below (see also the methods described incopending U.S. application Ser. No. 10/053,355, filed Nov. 8, 2001, thedisclosure of which is incorporated herein by reference).

7.2.1.1 Preparation of STEMPRO-34 Complete Medium

To prepare STEMPRO-34 complete medium (“CM”), 250 mL STEMPRO-34™ serumfree medium (“SFM”; GibcoBRL, Catalog No. 10640) was added to a filterflask. To this was added 13 mL STEMPRO-34 Nutrient Supplement (“NS”;GibcoBRL, Catalog No. 10641) (prepared as described in more detail,below). The NS container was rinsed with approximately 10 mL SFM and therinse added to the filter flask. Following addition of 5 mL L-glutamine(200 mM; Mediatech, Catalog No. MT 25-005-CI and 5 mL 100×penicillin/streptomycin (“pen-strep”; HyClone, Catalog No. SV30010), thevolume was brought to 500 mL with SFM and the solution was filtered.

The most variable aspect of preparing the CM is the method by which theNS is thawed and mixed prior to addition to the SFM. The NS should bethawed in a 37° C. water bath and swirled, not vortexed or shaken, untilit is completely in solution. While swirling, take note whether thereare any lipids that are not yet in solution. If lipids are present andthe NS is not uniform in appearance, return it to the water bath andrepeat the swirling process until it is uniform in appearance. Sometimesthis component goes into solution immediately, sometimes after a coupleof swirling cycles, and sometimes not at all. If, after a couple ofhours, the NS is still not in solution, discard it and thaw a freshunit. NS that appears non-uniform after thaw should not be used.

7.2.1.2 Expansion of CD34+ Cells

A starting population of CD34-positive (CD34+) cells of relatively smallnumber (1-5×10⁶ cells) was expanded to a relatively large number ofCD34-negative progenitor cells (about 2-4×10⁹ cells) using the culturemedia and methods described below. The CD34+ cells (from a single donor)were obtained from Allcells (Berkeley, Calif.). Because there is adegree of variation in the quality and number of CD34+ cells thatAllcells typically provides, the newly delivered cells were transferredto a 15 mL conical tube and brought up to 10 mL in CM prior to use.

On day 0, a cell count was performed on the viable (phase-bright) cellsand the cells were spun at 1200 rpm to pellet. The cells wereresuspended to a density of 275,000 cells/mL with CM containing 200ng/mL recombinant human Stem Cell Factor (“SCF”; Peprotech, Catalog No.300-07) and 20 ng/mL human flt-3 ligand (Peprotech, Catalog No. 300-19)(“CM/SCF/flt-3 medium”). On about day 4 or 5, the density of the culturewas checked by performing a cell count and the culture was diluted to adensity of 275,000 cells/mL with fresh CM/SCF/flt-3 medium. On about day7, the culture was transferred to a sterile tube and a cell count wasperformed. The cells were spun at 1200 rpm and resuspended to a densityof 275,000 cells/mL with fresh CM/SCF/flt-3 medium.

This cycle was repeated, starting from day 0, a total of 3-5 times overthe expansion period.

When the culture is large and being maintained in multiple flasks and isto be resuspended, the contents of all of the flasks are combined into asingle container prior to performing a cell count. This ensures that anaccurate cell count is achieved and provides for a degree of uniformityof treatment for the entire population. Each flask is checked separatelyfor contamination under the microscope prior to combining to preventcontamination of the entire population.

Between days 17-24, the culture can begin to go into decline (i.e.,approximately 5-10% of the total number of cells die) and fail to expandas rapidly as before. The cells are then monitored on a daily basisduring this time, as complete failure of the culture can take place inas little as 24 hours. Once the decline has begun, the cells arecounted, spun down at 850 rpm for 15 minutes, and resuspended at adensity of 350,000 cells/mL in CM/SCF/flt-3 medium to induce one or twomore divisions out of the culture. The cells are monitored daily toavoid failure of the culture.

When greater than 15% cell death is evident in the progenitor cellculture and some debris is present in the culture, the CD34-negativeprogenitor cells are ready to be differentiated.

7.2.1.3 Differentiation of CD34-Negative Progenitor Cells into MucosalMast Cells

A second phase is performed to convert the expanded CD34-negativeprogenitor cells into differentiated mucosal mast cells. These mucosalcultured human mast cells (“CHMC”) are derived from CD34+ cells isolatedfrom umbilical cord blood and treated to form a proliferated populationof CD34-negative progenitor cells, as described above. To produce theCD43-negative progenitor cells, the resuspension cycle for the culturewas the same as that described above, except that the culture was seededat a density of 425,000 cells/mL and 15% additional media was added onabout day four or five without performing a cell count. Also, thecytokine composition of the medium was modified such that it containedSCF (200 ng/mL) and recombinant human IL-6 (200 ng/mL; Peprotech,Catalog No. 200-06 reconstituted to 100 ug/mL in sterile 10 mM aceticacid) (“CM/SCF/IL-6 medium”).

Phases I and II together span approximately 5 weeks. Some death anddebris in the culture is evident during weeks 1-3 and there is a periodduring weeks 2-5 during which a small percentage of the culture is nolonger in suspension, but is instead attached to the surface of theculture vessel.

As during Phase I, when the culture is to be resuspended on day seven ofeach cycle, the contents of all flasks are combined into a singlecontainer prior to performing a cell count to ensure uniformity of theentire population. Each flask is checked separately for contaminationunder the microscope prior to combining to prevent contamination of theentire population.

When the flasks are combined, approximately 75% of the volume istransferred to the communal container, leaving behind about 10 mL or soin the flask. The flask containing the remaining volume was rappedsharply and laterally to dislodge the attached cells. The rapping wasrepeated at a right angle to the first rap to completely dislodge thecells.

The flask was leaned at a 45 degree angle for a couple of minutes beforethe remaining volume was transferred to the counting vessel. The cellswere spun at 950 rpm for 15 min prior to seeding at 35-50 mL per flask(at a density of 425,000 cells/mL).

7.2.1.4 Differentiation of CD34-Negative Progenitor Cells intoConnective Tissue-Type Mast Cells

A proliferated population of CD34-negative progenitor cells is preparedas above and treated to form a tryptase/chymase positive (connectivetissue) phenotype. The methods are performed as described above formucosal mast cells, but with the substitution of IL-4 for IL-6 in theculture medium. The cells obtained are typical of connective tissue mastcells.

7.2.1.5 Differentiation of CD34-Negative Progenitor Cells into BasophilCells

A proliferated population of CD34-negative progenitor cells is preparedas described in Section 7.2.1.3, above, and used to form a proliferatedpopulation of basophil cells. The CD34-negative cells are treated asdescribed for mucosal mast cells, but with the substitution of IL-3 (at20-50 ng/mL) for IL-6 in the culture medium.

7.2.2 CHMC Low Cell Density IgE Activation: Tryptase and LTC4 Assays

To duplicate 96-well U-bottom plates (Costar 3799) add 65 ul of compounddilutions or control samples that have been prepared in MT [137 mM NaCl,2.7 mM KCl, 1.8 mM CaCl₂, 1.0 mM MgCl₂, 5.6 mM Glucose, 20 mM Hepes (pH7.4), 0.1% Bovine Serum Albumin, (Sigma A4503)] containing 2% MeOH and1% DMSO. Pellet CHMC cells (980 rpm, 10 min) and resuspend in pre-warmedMT. Add 65 ul of cells to each 96-well plate. Depending on thedegranulation activity for each particular CHMC donor, load 1000-1500cells/well. Mix four times followed by a 1 hr incubation at 37° C.During the 1 hr incubation, prepare 6× anti-IgE solution [rabbitanti-human IgE (1 mg/ml, Bethyl Laboratories A80-109A) diluted 1:167 inMT buffer]. Stimulate cells by adding 25 ul of 6× anti-IgE solution tothe appropriate plates. Add 25 ul MT to un-stimulated control wells. Mixtwice following addition of the anti-IgE. Incubate at 37° C. for 30minutes. During the 30 minute incubation, dilute the 20 mM tryptasesubstrate stock solution [(Z-Ala-Lys-Arg-AMC 2TFA; Enzyme SystemsProducts, #AMC-246)] 1:2000 in tryptase assay buffer [0.1 M Hepes (pH7.5), 10% w/v Glycerol, 10 uM Heparin (Sigma H-4898) 0.01% NaN₃]. Spinplates at 1000 rpm for 10 min to pellet cells. Transfer 25 ul ofsupernatant to a 96-well black bottom plate and add 100 ul of freshlydiluted tryptase substrate solution to each well. Incubate plates atroom temperature for 30 min. Read the optical density of the plates at355 nm/460 nm on a spectrophotometric plate reader.

Leukotriene C4 (LTC4) is also quantified using an ELISA kit onappropriately diluted supernatant samples (determined empirically foreach donor cell population so that the sample measurement falls withinthe standard curve) following the supplier's instructions.

7.2.3 CHMC High Cell Density IgE Activation: Degranulation (Tryptase,Histamine), Leukotriene (LTC4), and Cytokine (TNFalpha, IL-13) Assays

Cultured human mast cells (CHMC) are sensitized for 5 days with IL-4 (20ng/ml), SCF (200 ng/ml), IL-6 (200 ng/ml), and Human IgE (CP 1035K fromCortx Biochem, 100-500 ng/ml depending on generation) in CM medium.After sensitizing, cells are counted, pelleted (1000 rpm, 5-10 minutes),and resuspended at 1-2×10⁶ cells/ml in MT buffer. Add 100 ul of cellsuspension to each well and 100 ul of compound dilutions. The finalvehicle concentration is 0.5% DMSO. Incubate at 37° C. (5% CO₂) for 1hour. After 1 hour of compound treatment, stimulate cells with 6×anti-IgE. Mix wells with the cells and allow plates to incubate at 37°C. (5% CO₂) for one hour. After 1 hour incubation, pellet cells (10minutes, 1000 RPM) and collect 200 ul per well of the supernatant, beingcareful not to disturb pellet. Place the supernatant plate on ice.During the 7-hour step (see next) perform tryptase assay on supernatantthat had been diluted 1:500. Resuspend cell pellet in 240 ul of CM mediacontaining 0.5% DMSO and corresponding concentration of compound.Incubate CHMC cells for 7 hours at 37° C. (5% CO₂). After incubation,pellet cells (1000 RPM, 10 minutes) and collect 225 ul per well andplace in −80° C. until ready to perform ELISAS. ELISAS are performed onappropriately diluted samples (determined empirically for each donorcell population so that the sample measurement falls within the standardcurve) following the supplier's instructions.

7.2.4 Results

The results of low density CHMC assays are provided in Table 1. In Table1, all reported values are IC₅₀s (in μM). Most compounds tested hadIC₅₀s of less than 10 μM, with many exhibiting IC₅₀s in thesub-micromolar range. In Table 1, all reported values are IC₅₀s (in μM).A value of “−” indicates an IC₅₀>10 μM, with no measurable activity at a10 μM concentration. Most compounds tested had IC₅₀s of less than 10 μM,with many exhibiting IC₅₀s in the sub-micromolar range. A value of “+”indicates an IC₅₀<10 μM. Of the compounds tested, BMMC values arecomparable to those noted for the CHMC results.

7.3 the 2,4-Pyrimidinediamine Compounds of the Invention SelectivelyInhibit the Upstream IgE Receptor Cascade

To confirm that many of the 2,4-pyrimidinediamine compounds of theinvention exert their inhibitory activity by blocking or inhibiting theearly IgE receptor signal transduction cascade, several of the compoundswere tested in cellular assays for ionomycin-induced degranulation, asdescribed below.

7.3.1 CHMC Low Cell Density Ionomycin Activation: Tryptase Assay

Assays for ionomycin-induced mast cell degranulation were carried out asdescribed for the CHMC Low Density IgE Activation assays (Section 7.2.2,supra), with the exception that during the 1 hour incubation, 6×ionomycin solution [5 mM ionomycin (Sigma I-0634) in MeOH (stock)diluted 1:416.7 in MT buffer (2 μM final)] was prepared and cells werestimulated by adding 25 μM of the 6× ionomycin solution to theappropriate plates.

7.3.2 Results

The results of the ionomycin-induced degranulation assays, reported asIC50 values (in μM) are provided in Table 1. Of the active compoundstested (i.e., those that inhibit IgE-induced degranulation), the vastmajority do not inhibit ionomycin-induced degranulation, confirming thatthese active compounds selectively inhibit the early (or upstream) IgEreceptor signal transduction cascade. In Table 1, all reported valuesare IC₅₀s (in μM). A value of “−” indicates an IC₅₀>10 μM, with nomeasurable activity at a 10 μM concentration. A value of “+” indicatesan IC₅₀<10 μM.

7.4 2,4-Pyrimidinediamine Compounds Inhibit Syk Kinase in BiochemicalAssays

Many of the 2,4-pyrimidinediamine compounds were tested for the abilityto inhibit Syk kinase catalyzed phosphorylation of a peptide substratein a biochemical fluorescenced polarization assay with isolated Sykkinase. In this experiment, Compounds were diluted to 1% DMSO in kinasebuffer (20 mM HEPES, pH 7.4, 5 mM MgCl₂, 2 mM MnCl₂, 1 mM DTT, 0.1 mg/mLacetylated Bovine Gamma Globulin). Compound in 1% DMSO (0.2% DMSO final)was mixed with ATP/substrate solution at room temperature. Syk kinase(Upstate, Lake Placid N.Y.) was added to a final reaction volume of 20uL, and the reaction was incubated for 30 minutes at room temperature.Final enzyme reaction conditions were 20 mM HEPES, pH 7.4, 5 mM MgCl₂, 2mM MnCl₂, 1 mM DTT, 0.1 mg/mL acetylated Bovine Gamma Globulin, 0.125 ngSyk, 4 uM ATP, 2.5 uM peptide substrate (biotin-EQEDEPEGDYEEVLE-CONH2,SynPep Corporation). EDTA (10 mM final)/anti-phosphotyrosine antibody(1× final)/fluorescent phosphopeptide tracer (0.5× final) was added inFP Dilution Buffer to stop the reaction for a total volume of 40 uLaccording to manufacturer's instructions (PanVera Corporation) The platewas incubated for 30 minutes in the dark at room temperature. Plateswere read on a Polarion fluorescence polarization plate reader (Tecan).Data were converted to amount of phosphopeptide present using acalibration curve generated by competition with the phosphopeptidecompetitor provided in the Tyrosine Kinase Assay Kit, Green (PanVeraCorporation).

These data, shown in Table 1, demonstrate that most all of the compoundstested, inhibit Syk kinase phosphorylation with IC₅₀s in thesubmicromolar range. A vast majority of the compounds tested inhibit Sykkinase phosphorylation with IC₅₀s in the micromolar range. In Table 1,all reported values are IC₅₀s (in μM). A value of “−” indicates anIC₅₀>10 μM, with no measurable activity at a 10 μM concentration. Avalue of “+” indicates an IC₅₀<10 μM.

LD LD LD Tryptase, Tryptase, Tryptase, Compound Compound Physical CHMC,CHMC, CHMC, fp_syk, Number Name Data IgE, 3 pt IgE, 8 pt Iono, 3 pt 11pt 200 (S)-5-Fluoro-N2- (indazol-6-yl)-N4- (2-methyl-3-oxo-2H,4H- ¹H NMR(DMSO-d6): d 8.08 (d, 1H), 7.95 (s, 1H), 7.58 (d, 1H), 7.40 (m, +benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 1H), 7.25 (m, 3H), 6.94 (m,1H), 4.80 (m, 1H), 1.40 (s, 3H); LCMS: purity: 96%; MS (m/e): 406 (MH+).201 (S)-5-Fluoro-N2- (1-methylindazol-6-yl)-N4- (2-methyl-3-oxo- ¹H NMR(DMSO-d6): d 8.17 (d, 1H), 8.08 (s, 1H), 7.80 (s, 1H), 7.52 +2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine (m, 1H), 7.32 (m, 1H),7.17 (m, 2H), 6.94 (m, 1H), 4.60 (m, 1H), 3.77 (s, 3H), 1.45 (s, 3H);LCMS: purity: 94%; MS (m/e): 420 (MH+). 202 (S)-N2-(3,5-Dimethylphenyl)-5-fluoro-N4- (2-methyl-3-oxo- ¹H NMR (DMSO-d6): d8.01 (d, 1H), 7.28 (m, 2H), 7.20 (s, 2H), 6.95 +2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine (m, 1H), 6.58 (s, 1H),4.63 (m, 1H), 3.77 (s, 3H), 2.07 (s, 6H), 1.42 (d, 3H); LCMS: purity:92%; MS (m/e): 393 (MH+). 203 N4-(3,4-Dihydro-3,3-dimethyl-2H,4H-benz[1,4]oxazin-6-yl)-N2- ¹H NMR(DMSO-d6): d 8.02 (d, 1H), 6.98 (m, 2H), 6.90 (m, 2H), 6.80 + +(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (m, 1H), 6.03 (s,1H), 3.72 (s, 2H), 3.60 (s, 6H), 1.05 (s, 6H); LCMS: purity: 96%; MS(m/e): 425 (MH+). 204 (R)-N2- (3,5-Dimethylphenyl)-5-fluoro-N4-(2-methyl-3-oxo- ¹H NMR (DMSO-d6): d 8.01 (d, 1H), 7.28 (m, 2H), 7.20(s, 2H), 6.95 + 2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine (m,1H), 6.58 (s, 1H), 4.63 (m, 1H), 3.77 (s, 3H), 2.07 (s, 6H), 1.42 (d,3H); LCMS: purity: 92%; MS (m/e): 393 (MH+). 205 (R)-5-Fluoro-N2-[6-(2-hydroxyethyl)-2,3-dihydropyrrolo[1,2,3- ¹H NMR (MeOD-d4): d 7.75 (d,1H), 7.38 (m, 1H), 7.02 (m, 3H), 6.78 + d,e]benzoxazin-8-yl]-N4-(2-methyl-3-oxo-2H,4H- (m, 2H), 4.54 (m, 1H), 4.4 (m, 2H), 4.14 (m, 2H),3.62 (m, 2H), 3.62 benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine (m, 2H),2.80 (m, 2H), 1.41 (d, 3H); LCMS: purity: 93%; MS (m/e): 491 (MH+). 206N4- (3,4-Dihydro-3,3-dimethyl-2H,4H-benz[1,4]oxazin-6-yl)-5- ¹H NMR(MeOD-d4): d 7.62 (d, 1H), 7.04 (s, 1H), 6.98 (m, 2H), 6.75 +fluoro-N2-[6- (2-hydroxyethyl)-2,3-dihydropyrrolo[1,2,3- (m, 1H), 6.59(m, 2H), 4.47 (m, 1H), 4.4 (m, 2H), 4.14 (m, 2H), 3.62d,e]benzoxazin-8-yl]-2,4-pyrimidinediamine (m, 4H), 2.80 (m, 2H), 1.07(s, 6H); LCMS: purity: 98%; MS (m/e): 491 (MH+). 207 (R)-N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4- (2-methyl-3- ¹H NMR (MeOD-d4): d7.98 (d, 1H), 7.82 (m, 2H), 7.48 (s, 1H), 7.41 +oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine (m, 3H), 7.25 (dd,1H), 7.15 (m, 3H), 6.94 (d, 1H), 4.62 (q, 1H), 3.82 Benzene SulfonicAcid Salt (s, 3H), 1.50 (d, 3H); LCMS: purity: 97%; MS (m/e): 430 (MH+).208 (R)-N2- (3-Chloro-4-methoxyphenyl)-5-fluoro-N4- (2-methyl-3- ¹H NMR(MeOD-d4): d 7.98 (d, 1H), 7.48 (s, 1H), 7.25 (dd, 1H), 7.15 +oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine (m, 3H), 6.94 (d,1H), 4.62 (q, 1H), 3.82 (s, 3H), 2.68 (s, 3H), 1.50 (d, MethanesulfonicAcid Salt 3H); LCMS: purity: 98%; MS (m/e): 430 (MH+). 209 (R)-N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4- (2-methyl-3- ¹H NMR (DMSO-d6): d8.19 (d, 1H), 7.62 (m, 1H), 7.38 (m, 1H), 7.21 +oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine (1S)- (m, 1H),7.12 (m, 2H), 6.91 (d, 1H), 4.62 (q, 1H), 3.82 (s, 3H), 3.40 (q,(+)-Camphorsulfonic Acid Salt 1H), 2.91 (m, 1H), 2.61 (m, 1H), 2.38 (m,1H), 2.22 (m, 1H), 1.85 (m, 2H), 1.40 (d, 3H), 1.31 (m, 2H), 1.03 (s,210 (R)-5-Fluoro-N2- (1-methylindazol-6-yl)-N4- (2-methyl-3-oxo- ¹H NMR(DMSO-d6): d 8.16 (d, 1H), 8.08 (s, 1H), 7.80 (s, 1H), 7.52 +2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine (m, 1H), 7.32 (m, 1H),7.17 (m, 2H), 6.94 (m, 1H), 4.60 (m, 1H), 3.77 (s, 3H), 1.45 (s, 3H);LCMS: purity: 97%; MS (m/e): 420 (MH+). 211 (R)-N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4- (2-methyl-3- ¹H NMR (DMSO-d6): d8.12 (d, 1H), 7.41 (dd, 1H), 7.22 (m, 3H), 6.97 + +oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine (m, 1H), 4.61 (q,1H), 3.78 (s, 3H), 1.40 (d, 3H); LCMS: purity: 97%; Hydrogen ChlorideSalt MS (m/e): 430 (MH+). 212 (R)-N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4- (2-methyl-3- ¹H NMR (DMSO-d6): d8.19 (d, 1H), 7.62 (m, 1H), 7.38 (m, 1H), 7.21 + +oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine (1R)- (m, 1H),7.12 (m, 2H), 6.91 (d, 1H), 4.62 (q, 1H), 3.82 (s, 3H), 3.40 (q,(−)-Camphorsulfonic Acid Salt 1H), 2.91 (m, 1H), 2.61 (m, 1H), 2.38 (m,1H), 2.22 (m, 1H), 1.85 (m, 2H), 1.40 (d, 3H), 1.31 (m, 2H), 1.03 (s,213 (R)-N2- (3-Chloro-4-methoxy-6-methylphenyl)-5-fluoro-N4- (2- ¹H NMR(DMSO-d6): d 8.17 (s, 1H), 7.98 (d, 1H), 7.43 (m, 1H), 7.32 + +methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- (m, 1H), 7.15 (s, 1H),6.95 (s, 1H), 6.72 (d, 1H), 4.58 (m, 1H), 3.90 (s, pyrimidinediamine3H), 2.17 (s, 3H), 1.38 (d, 3H); LCMS: purity: 97%; MS (m/e): 444 (MH+).214 (S)-N2- (3-Chloro-4-methoxy-6-methylphenyl)-5-fluoro-N4- (2- ¹H NMR(DMSO-d6): d 8.17 (s, 1H), 7.98 (d, 1H), 7.43 (m, 1H), 7.32 + + −methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- (m, 1H), 7.15 (s, 1H),6.95 (s, 1H), 6.72 (d, 1H), 4.58 (m, 1H), 3.90 (s, pyrimidinediamine3H), 2.17 (s, 3H), 1.38 (d, 3H); LCMS: purity: 99%; MS (m/e): 444 (MH+).215 (S)- (3-Chloro-4,6-dimethoxyphenyl)-5-fluoro-N4- (2-methyl-3- 1H NMR(DMSO-d6): d 1.38 (d, 3H), 3.82 (s, 3H), 3.90 (s, 3H), 4.58 + + −oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine (q, 1H), 6.85 (m,2H), 7.19 (m, 1H), 7.37 (m, 1H), 7.43 (m, 1H), 7.59 (s, 1H), 8.17 (m,2H) purity: 99%; MS (m/e): 460 (MH+). 216 N2-(3-Chloro-4-methoxy-6-methylphenyl)-N4- (3,4-dihydro-3,3- 1H NMR(DMSO-d6): d 1.38 (s, 6H), 2.17 (s, 3H), 3.64 (s, 3H), 3.81 + + −dimethyl-2H,4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4- (s, 3H), 6.48 (m,1H), 6.77 (m, 1H), 6.93 (m, 1H), 6.99 (m, 1H), pyrimidinediamine 7.41(s, 1H), 7.82 (d, 1H) purity: 99%; MS (m/e): 444 (MH+). 217 N4-(3,4-Dihydro-2H,4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-[3- ¹H NMR(DMSO-d6): d 8.19 (m, 1H), 8.15 (d, 1H), 7.78 (m, 1H), 7.39 + + −(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine (m, 2H), 6.90 (m, 1H), 6.47(m, 1H), 4.07 (m, 2H), 3.22 (m, 2H); LCMS: purity: 97%; MS (m/e): 405(MH+). 218 N4- (3,4-Dihydro-3,3-dimethyl-2H,4H-benz[1,4]oxazin-6-yl)-5-1H NMR (DMSO-d6): d 1.18 (s, 6H), 3.81 (s, 2H), 6.77 (m, 1H), + + −fluoro-N2-[3- (oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 6.93 (m, 1H),6.99 (m, 1H), 7.38 (m, 2H), 7.63 (m, 1H), 7.71 (m, 1H), 8.12 (s, 1H),8.22 (m, 2H) purity: 99%; MS (m/e): 433 (MH+). 219 5-Fluoro-N2-[3-(oxazol-2-yl)phenyl]-N4- (3-oxo-2H,4H- 1H NMR (DMSO-d6): d 4.50 (s, 2H),6.78 (m, 1H), 7.18 (m, 1H), + + −benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 7.23 (m, 1H), 7.38 (m, 2H),7.59 (m, 1H), 7.77 (m, 1H), 8.22 (m, 3H) purity: 99%; MS (m/e): 419(MH+). 220 5-Fluoro-N2-[3- (oxazol-2-yl)phenyl]-N4- (3-oxo-2H,4H- 1H NMR(DMSO-d6): d 4.50 (s, 2H), 6.78 (m, 1H), 7.18 (m, 1H), + + −benz[1,4]oxazin-7-yl)-2,4-pyrimidinediamine 7.23 (m, 1H), 7.41 (m, 2H),7.59 (m, 1H), 7.78 (m, 1H), 8.22 (m, 3H) purity: 97%; MS (m/e): 419(MH+). 221 5-Fluoro-N4-[2- (2-hydroxyethyl)-3-oxo-2H,4H-benz[1,4]oxazin-1H NMR (DMSO-d6): d 1.98 (m, 1H), 3.58 (m, 2H), 6.78 (m, 1H), + + −6-yl]-N2-[3- (oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 7.18 (m, 1H),7.38 (m, 3H), 7.57 (m, 1H), 7.79 (m, 1H), 8.22 (m, 2H) purity: 99%; MS(m/e): 463 (MH+). 222 N4-(3,4-Dihydro-2H,4H-Benz[1,4]oxazin-6-yl)-5-fluoro-N2-[4- ¹H NMR(DMSO-d6): d 8.29 (m, 1H), 8.17 (d, 1H), 7.76 (m, 1H), 7.59 + + −(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine (m, 3H), 6.90 (m, 1H), 6.77(m, 1H), 6.62 (m, 1H), 4.07 (m, 2H), 3.22 (m, 2H); LCMS: purity: 90%; MS(m/e): 405 (MH+). 223 N4-(3,4-Dihydro-3,3-dimethyl-2H,4H-benz[1,4]oxazin-6-yl)-5- 1H NMR(DMSO-d6): d 1.18 (s, 6H), 3.80 (s, 2H), 6.71 (m, 2H), + + −fluoro-N2-[4- (oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 6.95 (m, 1H),7.51 (s, 1H), 7.69 (m, 2H), 7.69 (m, 2H), 8.20 (d, 1H), 8.38 (s, 1H)purity: 95%; MS (m/e): 433 (MH+). 224 5-Fluoro-N2-[4-(oxazol-5-yl)phenyl]-N4- (3-oxo-2H,4H- 1H NMR (DMSO-d6): d 4.68 (s, 2H),6.98 (m, 2H), 7.22 (m, 1H), + + −benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 7.51 (s, 1H), 7.57 (m, 2H),7.78 (m, 2H), 8.28 (d, 1H), 8.38 (s, 1H) purity: 98%; MS (m/e): 419(MH+). 225 (S)-5-Fluoro-N4- (2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-¹H NMR (DMSO-d6): d 8.28 (s, 1H), 8.22 (d, 1H), 7.62 (m, 2H), 7.57 + + −N2-[4- (oxazol-5-yl-phenyl]-2,4-pyrimidinediamine (m, 2H), 7.49 (s, 1H),7.25 (m, 2H), 6.98 (m, 1H), 4.62 (q, 1H), 1.42 (d, 3H); LCMS: purity:88%; MS (m/e): 433 (MH+). 226 5-Fluoro-N2-[4- (oxazol-5-yl)phenyl]-N4-(3-oxo-2H,4H- 1H NMR (DMSO-d6): d 4.66 (s, 2H), 6.98 (m, 2H), 7.22 (m,1H), + + − benz[1,4]oxazin-7-yl)-2,4-pyrimidinediamine 7.51 (s, 1H),7.57 (m, 2H), 7.76 (m, 2H), 8.28 (d, 1H), 8.38 (s, 1H) purity: 92%; MS(m/e): 419 (MH+). 227 5-Fluoro-N4-[2-(2-hydroxyethyl)-3-oxo-2H,4H-benz[1,4]oxazin- 1H NMR (DMSO-d6): d 1.93(m, 2H), 3.58 (m, 2H), 4.62 (m, 1H), + + − + 6-yl]-N2-[4-(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 6.98 (m, 2H), 7.22 (m, 2H),7.51 (s, 1H), 7.57 (m, 2H), 7.76 (m, 2H), 8.28 (d, 1H), 8.38 (s, 1H)purity: 95%; MS (m/e): 463 (MH+). 228 N4-(3,4-Dihydro-4-methyl-2H-benz[1,4]oxazin-6-yl)-5-fluoro- ¹H NMR(DMSO-d6): d 8.29 (s, 1H), 8.15 (d, 1H), 7.76 (m, 1H), 7.57 + + − N2-[4-(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine (m, 3H), 6.88 (m, 1H), 6.77(m, 1H), 6.62 (m, 1H), 4.10 (m, 2H), 3.20 (m, 2H), 2.80 (s, 3H); LCMS:purity: 94%; MS (m/e): 419 (MH+). 229 N4-(3,4-Dihydro-4-methyl-2H-benz[1,4]oxazin-7-yl)-5-fluoro- ¹H NMR(DMSO-d6): d 8.37 (s, 1H), 8.19 (d, 1H),7.61 (m, 5H), 7.07 + + − N2-[4-(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine (m, 2H), 6.68 (m, 1H), 4.22(m, 2H), 3.22 (m, 2H), 2.81 (s, 3H); LCMS: purity: 94%; MS (m/e): 419(MH+). 230 5-Fluoro-N4- (4-methyl-3-oxo-2H-benz[1,4]oxazin-7-yl)-N2-[4-¹H NMR (DMSO-d6): d 8.36 (s, 1H), 8.20 (m, 1H), 8.19 (d, 1H), 7.77 − − −(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine (m, 2H), 7.54 (m, 2H), 7.37(s, 1H), 7.25 (m, 1H), 6.97 (m, 1H), 4.58 (s, 2H), 2.97 (s, 3H); LCMS:purity: 98%; MS (m/e): 433 (MH+). 231 5-Fluoro-N4-(4-methyl-3-oxo-2H-benz[1,4]oxazin-6-yl)-N2-[4- ¹H NMR (DMSO-d6): d 8.34(s, 1H), 8.20 (m, 1H), 8.17 (d, 1H), 7.71 − − −(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine (m, 2H), 7.54 (m, 2H), 7.33(s, 1H), 7.25 (m, 1H), 6.92 (m, 1H), 4.60 (s, 2H), 2.90 (s, 3H); LCMS:purity: 95%; MS (m/e): 433 (MH+). 232 N4-(3,4-Dihydro-2H,4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-[3- ¹H NMR(DMSO-d6): d 8.39 (m, 1H), 8.22 (d, 1H), 7.86 (m, 1H), 7.59 + + −(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine (m, 4H), 6.87 (m, 2H), 6.52(m, 1H), 4.09 (m, 2H), 3.23 (m, 2H); LCMS: purity: 90%; MS (m/e): 405(MH+). 233 N4- (3,4-Dihydro-3,3-dimethyl-2H,4H-benz[1,4]oxazin-6-yl)-5-¹H NMR (DMSO-d6): d 8.37 (s, 1H), 8.19 (d, 1H), 7.82 (m, 1H), 7.63 + + −fluoro-N2-[3- (oxazol-5-yl)phenyl]-2,4-pyrimidinediamine (m, 2H), 7.50(s, 1H), 7.38 (m, 1H), 6.87 (m, 1H), 6.65 (m, 2H), 3.82 (s, 2H), 1.19(s, 6H); LCMS: purity: 95%; MS (m/e): 433 (MH+). 234 5-Fluoro-N2-[3-(oxazol-5-yl)phenyl]-N4- (3-oxo-2H,4H- 1H NMR (DMSO-d6): d 4.42 (s, 2H),6.61 (m, 2H), 6.95 (m, 1H), + + −benz[1,4]oxazin-7-yl)-2,4-pyrimidinediamine 7.51 (s, 1H), 7.49 (m, 2H),7.59 (m, 2H), 8.20 (d, 1H), 8.38 (s, 1H) purity: 90%; MS (m/e): 419(MH+). 235 5-Fluoro-N4-[2- (2-hydroxyethyl)-3-oxo-2H,4H-benz[1,4]oxazin-1H NMR (DMSO-d6): d 1.93 (m, 2H), 3.58 (m, 2H), 4.62 (m, 1H), + + −6-yl]-N2-[3- (oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 6.61 (m, 2H),6.95 (m, 1H), 7.51 (s, 1H), 7.49 (m, 2H), 7.59 (m, 2H), 8.20 (d, 1H),8.38 (s, 1H) purity: 90%; MS (m/e): 463 (MH+). 236 N4-(3,4-Dihydro-4-methyl-2H-benz[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 1.93 (m, 2H), 3.58 (m, 2H), 4.62 (m, 1H), + − N2-[3-(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 6.61 (m, 2H), 6.95 (m, 1H),7.51 (s, 1H), 7.49 (m, 2H), 7.59 (m, 2H), 8.20 (d, 1H), 8.38 (s, 1H)purity: 95%; MS (m/e): 419 (MH+). 237 N4-(3,4-Dihydro-4-methyl-2H-benz[1,4]oxazin-7-yl)-5-fluoro- 1H NMR(DMSO-d6): d 1.93 (m, 2H), 2.82 (s, 3H), 3.58 (m, 2H), + − N2-[3-(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 4.62 (m, 1H), 6.61 (m, 2H),6.95 (m, 1H), 7.51 (s, 1H), 7.49 (m, 2H), 7.59 (m, 2H), 8.20 (d, 1H),8.38 (s, 1H) purity: 95%; MS (m/e): 419 (MH+). 238 N4-(3,4-Dihydro-3,3-dimethyl-2H,4H-benz[1,4]oxazin-6-yl)-5- 1H NMR(DMSO-d6): d 1.38 (s, 6H), 3.81 (s, 2H), 6.71 (m, 2H), + + −fluoro-N2-[4- (oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 6.95 (m, 1H),7.51 (s, 1H), 7.69 (m, 2H), 7.69 (m, 2H), 8.20 (d, 1H), 8.38 (s, 1H)purity: 99%; MS (m/e): 433 (MH+). 239 5-Fluoro-N2-[4-(oxazol-2-yl)phenyl]-N4- (3-oxo-2H,4H- ¹H NMR (DMSO-d6): d 8.15 (d 1H),8.10 (s, 1H), 7.78 (m, 3H), 7.14 + + −benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine (m, 3H), 6.97 (m, 2H), 4.56(s, 2H); LCMS: purity: 98%; MS (m/e): 419 (MH+). 240 (S)-5-Fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)- ¹H NMR (DMSO-d6): d 8.25(m, 1H), 8.22 (d, 1H), 8.12 (m, 1H), 7.77 + + − N2-[4-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine (m, 2H), 7.34 (s, 1H), 7.23(m, 2H), 6.98 (m, 2H), 4.63 (q, 1H), 1.42 (d, 3H); LCMS: purity: 95%; MS(m/e): 433 (MH+). 241 5-Fluoro-N2-[4- (oxazol-2-yl)phenyl]-N4-(3-oxo-2H,4H- 1H NMR (DMSO-d6): d 4.45 (s, 2H), 6.71 (m, 2H), 6.95 (m,1H), − − benz[1,4]oxazin-7-yl)-2,4-pyrimidinediamine 7.51 (s, 1H), 7.69(m, 2H), 7.69 (m, 2H), 8.20 (d, 1H), 8.38 (s, 1H) purity: 95%; MS (m/e):419 (MH+). 242 5-Fluoro-N4-[2-(2-hydroxyethyl)-3-oxo-2H,4H-benz[1,4]oxazin- ¹H NMR (DMSO-d6): d 8.25(d 1H), 8.20 (d, 1H), 8.16 (s, 1H), 7.82 (m, + + − 6-yl]-N2-[4-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 3H), 7.35 (s, 1H), 7.20 (m,2H), 6.95 (m, 1H), 4.62 (m, 1H), 3.58 (m, 1H), 1.95 (m, 2H); LCMS:purity: 99%; MS (m/e): 463 (MH+). 243 N4-(2,3-Dihydro-4-methyl-2H-benz[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 1.93 (m, 2H), 2.80 (s, 3H), 3.58 (m, 2H), + + − N2-[4-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 4.62 (m, 1H), 6.71 (m, 2H),6.95 (m, 1H), 7.51 (s, 1H), 7.69 (m, 2H), 7.69 (m, 2H), 8.20 (d, 1H),8.38 (s, 1H) purity: 99%; MS (m/e): 419 (MH+). 244 5-Fluoro-N4-(4-methyl-3-oxo-2H-benz[1,4]oxazin-7-yl)-N2-[4- ¹H NMR (DMSO-d6): d 8.18(d, 1H), 8.14 (s, 1H), 7.82 (d, 2H), 7.56 − −(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine (m, 2H), 7.40 (m, 2H), 7.30(s, 1H), 6.95 (m, 1H), 4.62 (s, 2H), 2.78 (s, 3H); LCMS: purity: 99%; MS(m/e): 433 (MH+). 245 5-Fluoro-N4-(4-methyl-3-oxo-2H-benz[1,4]oxazin-6-yl)-N2-[4- ¹H NMR (DMSO-d6): d 8.20(d, 1H), 8.12 (s, 1H), 7.82 (d, 2H), 7.55 − −(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine (m, 2H), 7.40 (m, 2H), 7.33(s, 1H), 6.88 (m, 1H), 4.59 (s, 2H), 2.77 (s, 3H); LCMS: purity: 98%; MS(m/e): 433 (MH+). 246 5-Fluoro-N2-[3-(oxazol-5-yl)phenyl]-N4-[3-oxo-2H,4H- 1H NMR (DMSO-d6): d 4.45 (s, 2H),6.78 (m, 1H), 7.18 (m, 1H), + + −benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine 7.38 (m, 3H), 7.57 (m, 1H),7.79 (m, 1H), 8.22 (m, 2H) purity: 93%; MS (m/e): 419 (MH+). 247(S)-5-Fluoro-N4- (2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)- 1H NMR(DMSO-d6): d 1.38 (d, 3H), 4.58 (q, 1H), 6.78 (m, 1H), + + − N2-[3-(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 7.18 (m, 1H), 7.38 (m, 3H),7.57 (m, 1H), 7.79 (m, 1H), 8.22 (m, 2H) purity: 90%; MS (m/e): 433(MH+). 248 5-Fluoro-N4-[2- (2-hydroxyethyl)-3-oxo-2H,4H-benz[1,4]oxazin-1H NMR (DMSO-d6): d 1.93 (m, 2H), 3.58 (m, 2H), 4.62 (m, 1H), + + −7-yl]-N2-[3- (oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 6.88 (m, 2H),7.22 (m, 3H), 7.57 (m, 2H), 7.79 (m, 2H), 8.22 (m, 2H) purity: 99%; MS(m/e): 463 (MH+). 249 5-Fluoro-N4-[2-(2-hydroxyethyl)-3-oxo-2H,4H-benz[1,4]oxazin- 1H NMR (DMSO-d6): d 1.93(m, 2H), 3.58 (m, 2H), 4.62 (m, 1H), + − − 7-yl]-N2-[4-(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 6.71 (m, 2H), 6.95 (m, 1H),7.51 (s, 1H), 7.69 (m, 2H), 7.69 (m, 2H), 8.20 (d, 1H), 8.38 (s, 1H)purity: 99%; MS (m/e): 463 (MH+). 250 (R)-5-Fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)- 1H NMR (DMSO-d6): d d 1.38(d, 3H), 4.58 (q, 1H), 6.88 (m, 1H), + + + N2-[3-(oxazol-4-yl)phenyl]-2,4-pyrimidinediamine 7.22 (m, 4H), 7.57 (m, 1H),7.99 (m, 2H), 8.12 (m, 2H) purity: 95%; MS (m/e): 433 (MH+). 251(S)-5-Fluoro-N4- (2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)- 1H NMR(DMSO-d6): d d 1.38 (d, 3H), 4.58 (q, 1H), 6.88 (m, 1H), + + − N2-[3-(oxazol-4-yl)phenyl]-2,4-pyrimidinediamine 7.22 (m, 4H), 7.57 (m, 1H),7.99 (m, 2H), 8.12 (m, 2H) purity: 99%; MS (m/e): 433 (MH+). 252(R,S)-N2- (3,5-Dimethylphenyl)-5-fluoro-N4- 1H NMR (DMSO-d6): d 2.18 (s,6H), 2.25 (m, 2H) 3.75 (t, 2H) 4.58 +(tetrahydrofurano[2,3]-2H-benz[1,4]oxazin-6-yl)-2,4- (q, 1H), 6.52 (d,1H), 6.92 (dd, 2H), 7.37 (m, 3H), 8.12 (d, 1H) pyrimidinediamine purity:90%; MS (m/e): 406 (MH+). 253 N4-[3,4-Dihydro-2-(2-hydroxyethyl)-2H,4H-benz[1,4]oxazin-6- 1H NMR (DMSO-d6): d 1.88 (m,2H), 2.97 (m, 2H), 3.55 (m, 2H), + + − yl]-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 3.61 (s, 6H), 4.08(q, 1H), 6.02 (m, 1H), 6.58 (d, 1H), 6.96 (m, 5H), 8.02 (d, 1H) purity:96%; MS (m/e): 442 (MH+). 254 5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]- 1H NMR (DMSO-d6): d 2.62 (d,3H), 3.32 (s, 2H), 4.37 (s, 2H), + + − N4-(3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4- 6.60 (m, 1H), 7.22 (m, 3H),7.37 (m, 1H), 7.43 (m, 1H), 8.02 (m, 1H), pyrimidinediamine 8.22 (d, 1H)purity: 94%; MS (m/e): 455 (MH+). 255 N4-[2,3-Dihydro-2-(2-hydroxyethyl)-2H,4H-benz[1,4]oxazin-6- 1H NMR (DMSO-d6): d 1.88 (m,2H), 2.18 (s, 6H), 2.97 (m, 2H), + + − yl]-N2-(3,5-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine 3.58 (m, 2H), 4.09(q, 1H), 6.19 (m, 1H), 6.42 (m, 1H), 6.58 (m, 1H), 6.81 (m, 2H), 7.22(s, 2H), 8.02 (d, 1H) purity: 97%; MS (m/e): 410 (MH+). 256 N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4- (3-oxo-2H,4H- 1H NMR (DMSO-d6): d3.37 (s, 2H), 3.61 (s, 6H), 6.18 (m, 1H), + + −benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 6.75 (m, 2H), 7.22 (m,2H), 7.43 (m, 1H), 8.22 (d, 1H) purity: 98%; MS (m/e): 428 (MH+). 257N2- (3-Chloro-4-methoxyphenyl)-5-fluoro-N4- (3-oxo-2H,4H- 1H NMR(DMSO-d6): d 3.47 (s, 2H), 3.88 (s, 3H), 7.08 (m, 1H), + + −benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 7.25 (s, 2H), 7.42 (m,2H), 7.78 (m, 1H), 8.22 (d, 1H) purity: 99%; MS (m/e): 432 (MH+). 258N4- (3,4-Dihydro-2H,4H-benzo[1,4]thiazin-6-yl)-5-fluoro-N2-[3- 1H NMR(DMSO-d6): d 2.67 (d, 3H), 3.32 (m, 2H), 4.30 (s, 2H), 4.37 + + −(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- (m, 2H), 6.45 (m, 1H),6.88 (m, 1H), 6.96 (m, 2H), 7.13 (m, 1H), 7.23 pyrimidinediamine (m,2H), 8.02 (m, 2H) purity: 92%; MS (m/e): 441 (MH+). 259 5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]- 1H NMR (DMSO-d6): d 2.62 (d,3H), 3.11 (s, 3H), 3.32 (s, 2H), 4.37 + + − N4-(4-methyl-3-oxo-2H-benzo[1,4]thiazin-6-yl)-2,4- (s, 2H), 6.60 (m, 1H),7.22 (m, 3H), 7.37 (m, 1H), 7.43 (m, 1H), 8.02 pyrimidinediamine (m,1H), 8.22 (d, 1H) purity: 95%; MS (m/e): 469 (MH+). 260 N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4- (4-methyl-3-oxo-2H- 1H NMR (DMSO-d6):d 3.11 (s, 3H), 3.32 (s, 2H), 3.58 (s, 6H), + + −benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 6.18 (m, 1H), 6.75 (m,2H), 7.32 (m, 3H), 7.63 (m, 2H), 8.22 (d, 1H) purity: 98%; MS (m/e): 442(MH+). 261 N2- (3-Benzothioamide)-5-fluoro-N4- (3-oxo-2H,4H- 1H NMR(DMSO-d6): d 4.58 (s, 2H), 6.98 (m, 1H), 7.19 (m, 2H), + −benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 7.39 (m, 3H), 7.93 (m, 1H),8.19 (d, 1H) purity: 90%; MS (m/e): 411 (MH+). 262 N2-(3-Benzothioamide)-5-fluoro-N4-[2- (2-hydroxyethyl)-3-oxo- 1H NMR(DMSO-d6): 1.91 (m, 2H), 3.54 (m, 2H), 4.63 (m, 1H), 6.98 + −2H,4H-benz[1,4]oxazin-6-yl]-2,4-pyrimidinediamine (m, 1H), 7.19 (m, 2H),7.39 (m, 3H), 7.93 (m, 1H), 8.19 (d, 1H) purity: 93%; MS (m/e): 455(MH+). 263 N2- (3,5-Dimethoxyphenyl)-N4- (dioxide-2-methyl-1,1,3-trioxo-1H NMR (DMSO-d6): d 1.42 (d, 3H), 3.63 (s, 6H), 4.69 (q, 1H), 6.14 + + +4H-benzo[1,4]thiazin-6-yl)-5-fluoro-2,4-pyrimidinediamine (s, 1H), 6.92(m, 2H), 7.72 (s, 2H), 7.92 (m, 2H), 8.27 (d, 1H) purity: 99%; MS (m/e):474 (MH+). 264 N2- (3,5-Dimethylphenyl)-5-fluoro-N4-(2-methyl-1,1,3-trioxo- 1H NMR (DMSO-d6): d 1.42 (d, 3H), 2.18 (s, 6H),4.72 (q, 1H), 6.64 + + +2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine (m, 1H), 7.21 (m,2H), 7.72 (s, 2H), 7.68 (m, 2H), 8.27 (d, 1H) purity: 99%; MS (m/e): 442(MH+). 265 5-Fluoro-N2- (indazol-6-yl)-N4- (2-methyl-1,1,3-trioxo-2H,4H-1H NMR (DMSO-d6): d 1.42 (d, 3H), 4.79 (q, 1H), 7.23 (m, 1H), 7.60 + + +benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine (m, 1H), 7.77 (m, 1H),7.82 (m, 3H), 8.16 (m, 1H), 8.27 (d, 1H) purity: 94%; MS (m/e): 454(MH+). 266 5-Fluoro-N4-(2-methyl-1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6- 1H NMR (DMSO-d6): d1.42 (d, 3H), 3.66 (s, 9H), 4.70 (q, 1H), 7.04 + + + yl)-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine (m, 2H), 7.72 (s, 2H),7.72 (m, 3H), 8.22 (d, 1H) purity: 96%; MS (m/e): 504 (MH+). 267 N2-(3,5-Dimethoxyphenyl)-N4- (2,2-dimethyl-1,1,3-trioxo-4H- LCMS: ret time12.32 min purity: 100%; MS (m/e): 488 (MH⁺) + +benzo[1,4]thiazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 268 N2-(3,5-Dimethylphenyl)-N4- (2,2-dimethyl-1,1,3-trioxo-4H- LCMS: ret time13.35 min purity: 99%; MS (m/e): 456 (MH+) + +benzo[1,4]thiazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 269 N4-(2,2-Dimethyl-1,1,3-trioxo-4H-benzo[thiazin-6-yl)-5-fluoro- LCMS: rettime 11.28 min purity: 99%; MS (m/e): 518 (MH+) + + 2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 270 N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4- (2-methyl-3-oxo- LCMS: ret time 11.69min purity: 95%; MS (m/e): 442 (MH+) +2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 271 N2-(3,5-Dimethylphenyl)-5-fluoro-N4- (2-methyl-3-oxo-2H,4H- LCMS: ret time12.12 min purity: 98%; MS (m/e): 410 (MH+) +benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 272 5-Fluoro-N4-(2-methyl-3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)- LCMS: ret time 10.44 minpurity: 99%; MS (m/e): 472 (MH+) + N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 273 N4-(2,2-Dimethyl-1,1,3-trioxo-4H-benzo[1,4]thiazin-6-yl)-5- LCMS: ret time10.49 min purity: 95%; MS (m/e): 468 (MH+) + fluoro-N2-(indazol-6-yl)-2,4-pyrimidinediamine 274 N4-(2,2-Dimethyl-1,1,3-trioxo-4H-benzo[1,4]thiazin-6-yl)-5- LCMS: ret time8.66 min purity: 96%; MS (m/e): 468 (MH+) + fluoro-N2-(indazol-5-yl)-2,4-pyrimidinediamine 275 N4-(2,2-Dimethyl-1,1,3-trioxo-4H-benzo[1,4]thiazin-6-yl)-5- LCMS: ret time10.16 min purity: 93%; MS (m/e): 515 (MH+) + fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]- 2,4-pyrimidinediamine 276N2- (3-Chloro-4-methoxyphenyl)-N4- (2,2-dimethyl-1,1,3-trioxo- LCMS: rettime 12.66 min purity: 99%; MS (m/e): 492 (MH+) +4H-benzo[thiazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 277 5-Fluoro-N2-(indazol-6-yl)-N4- (2-methyl-3-oxo-2H,4H- LCMS: ret time 9.40 minpurity: 95%; MS (m/e): 422 (MH+) +benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 278 5-Fluoro-N2-(indazol-5-yl)-N4- (2-methyl-3-oxo-2H,4H- LCMS: ret time 8.23 minpurity: 98%; MS (m/e): 422 (MH+) +benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 279 5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]- LCMS: ret time 9.51 minpurity: 96%; MS (m/e): 469 (MH+) + N4-(2-methyl-3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4- pyrimidinediamine 280N2- (3-Chloro-4-methoxyphenyl)-5-fluoro-N4- (2-methyl-3-oxo- LCMS: rettime 11.77 min purity: 97%; MS (m/e): 446 (MH+) +2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 281 5-Fluoro-N2-(3-hydroxyphenyl)-N4- (3-oxo-2H,4H- LCMS: ret time 8.18 min purity: 99%;MS (m/e): 384 (MH+) + + benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine282 racemic-5-Fluoro-N2- (3-hydroxyphenyl)-N4- (2-methyl-3-oxo- LCMS:ret time 9.11 min purity: 99%; MS (m/e): 398 (MH+) +2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 283 racemic-N4-(2,2-Dimethyl-1,1,3-trioxo-4H-benzo[1,4]thiazin-6- LCMS: ret time 9.89min purity: 99%; MS (m/e): 444 (MH+) +yl)-5-fluoro-N2-[3-hydoxyphenyl]-2,4-pyrimidinediamine 284racemic-5-Fluoro-N2-[3-hydoxyphenyl]-N4- (2-methyl-1,1,3- LCMS: ret time9.33 min purity: 97%; MS (m/e): 430 (MH+) +trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 285racemic-5-Fluoro-N2-[3- (N- LCMS: ret time 9.44 min purity: 93%; MS(m/e): 501 (MH+) + methylamino)carbonylmethyleneoxyphenyl]-N4-(2-methyl- 1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 286 racemic-N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4- (2- LCMS: ret time 11.68 minpurity: 95%; MS (m/e): 478 (MH+) +methyl-1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4- pyrimidinediamine287 5-Fluoro-N4- (3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-N2- (3,4,5- LCMS:ret time 9.49 min purity: 99%; MS (m/e): 458 (MH+) +trimethoxyphenyl)-2,4-pyrimidinediamine 288 5-Fluoro-N2-(indazol-5-yl)-N4- (3-oxo-2H,4H-benzo[1,4]thiazin- LCMS: ret time 7.28min purity: 98%; MS (m/e): 408 (MH+) + 6-yl)-2,4-pyrimidinediamine 289N2- (3-Chloro-4-methoxyphenyl)-N4- (2,2-dimethyl-3-oxo-4H- LCMS: rettime 12.45 min purity: 97%; MS (m/e): 460 (MH+) +benzo[thiazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 290 N2-(3,5-Dimethoxyphenyl)-N4- (2,2-dimethyl-3-oxo-4H- LCMS: ret time 12.81min purity: 99%; MS (m/e): 456 (MH+) +benzo[1,4]thiazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 291 N4-(2,2-Dimethyl-3-oxo-4H-benzo[1,4]thiazin-6-yl)-N2- (3,5- LCMS: ret time13.44 min purity: 99%; MS (m/e): 424 (MH+) +dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine 292 N4-(2,2-dimethyl-3-oxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro-N2- LCMS: rettime 11.86 min purity: 99%; MS (m/e): 486 (MH+) +(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 293 N4-(2,2-Dimethyl-3-oxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro- LCMS: ret time10.39 min purity: 99%; MS (m/e): 412 (MH+) + N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine 294 N4-(2,2-Dimethyl-3-oxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro- LCMS: ret time10.04 min purity: 97%; MS (m/e): 483 (MH+) + + N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- pyrimidinediamine 295N4- (2,2-Dimethyl-3-oxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro- LCMS: rettime 10.54 min purity: 96%; MS (m/e): 436 (MH+) + + + N2-(indazol-6-yl)-2,4-pyrimidinediamine 296 racemic-5-Fluoro-N2-(3-fluoro-4-methoxyphenyl)-N4- (2- LCMS: ret time 11.91 min purity: 96%;MS (m/e): 462 (MH+) + +methyl-1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4- pyrimidinediamine297 N4- (2,2-Dimethyl-1,1,3-trioxo-4H-benzo[1,4]thiazin-6-yl)-5- LCMS:ret time 12.11 min purity: 96%; MS (m/e): 476 (MH+) + + fluoro-N2-(3-fluoro-4-methoxyphenyl)-2,4-pyrimidinediamine 298racemic-5-Fluoro-N2- (3-fluoro-4-methoxyphenyl)-N4- (2- LCMS: ret time11.29 min purity: 98%; MS (m/e): 430 (MH+) + +methyl-3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4- pyrimidinediamine 299N4- (2,2-Dimethyl-3-oxo-4H-benzo[thiazin-6-yl)-5-fluoro-N2- (3- LCMS:ret time 12.14 min purity: 99%; MS (m/e): 444 (MH+) + +fluoro-4-methoxyphenyl)-2,4-pyrimidinediamine 300 5-Fluoro-N2-(3-fluoro-4-methoxyphenyl)-N4- (3-oxo-2H,4H- LCMS: ret time 10.56 minpurity: 97%; MS (m/e): 415 (MH+) + +benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 301 N2-(3,5-Dimethylphenyl)-5-fluoro-N4- (3-oxo-2H,4H- LCMS: ret time 11.76 minpurity: 98%; MS (m/e): 396 (MH+) + +benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 302 N2-(3,5-Dimethylphenyl)-5-fluoro-N4- (1,1,3-trioxo-2H,4H- LCMS: ret time10.72 min purity: 96%; MS (m/e): 428 (MH+) +benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 303 N2-(3,5-Dimethoxylphenyl)-5-fluoro-N4- (1,1,3-trioxo-2H,4H- LCMS: ret time10.06 min purity: 95%; MS (m/e): 460 (MH+) +benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 304 N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4- (1,1,3-trioxo- LCMS: ret time10.13 min purity: 97%; MS (m/e): 464 (MH+) +2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 305 5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]- LCMS: ret time 8.40 minpurity: 97%; MS (m/e): 487 (MH+) + N4-(1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4- pyrimidinediamine 3065-Fluoro-N2- (3,4,5-triimethoxylphenyl)-N4- (1,1,3-trioxo-2H,4H- LCMS:ret time 9.19 min purity: 95%; MS (m/e): 490 (MH+) +benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 307 5-Fluoro-N2-(indazol-6-yl)-N4- (1,1,3-trioxo-2H,4H- LCMS: ret time 8.33 min purity:91%; MS (m/e): 440 (MH+) + benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine308 5-Fluoro-N2- (3-hydroxyphenyl)-N4- (1,1,3-trioxo-2H,4H- LCMS: rettime 8.07 min purity: 96%; MS (m/e): 416 (MH+) +benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 309 5-Fluoro-N2-(3-fluoro-4-methoxyphenyl)-N4- (1,1,3-trioxo- LCMS: ret time 9.74 minpurity: 95%; MS (m/e): 448 (MH+) +2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 310 5-Fluoro-N2-(indazol-5-yl)-N4- (1,1,3-trioxo-2H,4H- LCMS: ret time 7.40 min purity:94%; MS (m/e): 440 (MH+) + benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine311 N4- (2,2-Dimethyl-3-oxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro- LCMS:ret time 10.15 min purity: 99%; MS (m/e): 450 (MH+) + + N2-(1-methylindazol-6-yl)-2,4-pyrimidinediamine 312 N4-(2,2-Dimethyl-3-oxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro- LCMS: ret time10.54 min purity: 100%; MS (m/e): 436 (MH+) N2-(indazol-6-yl)-2,4-pyrimidinediamine Trifuoro Acetate Salt 313N2-Chloro-5-fluoro-N4- (3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-4- LCMS: rettime 5.58 min purity: 95%; MS (m/e): 311 (MH+) + pyrimidineamine 314racemic-N2-Chloro-5-fluoro-N4- (2-methyl-3-oxo-2H,4H- LCMS: ret time11.18 min purity: 95%; MS (m/e): 325 (MH+) +benzo[1,4]thiazin-6-yl)-4-pyrimidineamine 315 N2-Chloro-5-fluoro-N4-(1,1,3-trioxo-2H,4H-benzo[1,4]thiazin- LCMS: ret time 10.03 min purity:95%; MS (m/e): 343 (MH+) − 6-yl)-4-pyrimidineamine 316 N2-Chloro-N4-(2,2,-dimethyl-3-oxo-4H-benzo[1,4]thiazin-6-yl)- LCMS: ret time 12.29min purity: 95%; MS (m/e): 339 (MH+) + 5-fluoro-4-pyrimidineamine 317racemic-N2-Chloro-5-fluoro-N4- (2-methyl-1,1,3-trioxo-2H,4H- LCMS: rettime 10.16 min purity: 96%; MS (m/e): 357 (MH+) −benzo[1,4]thiazin-6-yl)-4-pyrimidineamine 318 N2-Chloro-N4-(2,2-dimethyl-1,1,3-trioxo-4H-benzo[1,4]thiazin- LCMS: ret time 10.50min purity: 96%; MS (m/e): 371 (MH+) + 6-yl)-5-fluoro-4-pyrimidineamine319 N4-[benzoxathiazin-3 (4H)-one-6-yl]2-chloro-5-fluoro-4- LCMS: rettime 6.40 min purity: 99%; MS (m/e): 296 (MH+) + pyrimidineamine 320N2-Chloro-N4- (3,3-dimethyl-1,4-benzoxazin-6-yl)-5-fluoro- LCMS: rettime 12.20 min purity 99% MS (m/e): 309 (MH⁺) + pyrimidineamine 324 N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4- (3- 1H NMR (DMSO-d6): d 9.57 (bs,1H), 9.21 (bs, 1H), 8.16 (d, J = 3.6 +trifluoromethoxyphenyl)-2,4-pyrimidinediamine Hz, 1H), 8.01 (d, J = 8.1Hz, 1H), 7.75 (s, 1H), 7.40 (t, J = 8.1 Hz, 1H), 7.01 (d, J = 8.4 Hz,1H), 6.91 (d, J = 2.1 Hz, 2H), 6.09-6.06 (m, 1H), 3.65 (s, 6H); 19F NMR(282 MHz, DMSO-d6): −57.17, −163.27; LCMS: purity: 99%; MS (m/e): 425(MH+) 325 N2- (3,5-Dimethylphenyl)-5-fluoro-N4- (3- ¹H NMR (DMSO-d6): d9.54 (bs, 1H), 9.12 (bs, 1H), 8.15 (dd, J = 1.8 +trifluoromethoxyphenyl)-2,4-pyrimidinediamine and 3.6 Hz, 1H), 7.96 (d,J = 8.1 Hz, 1H), 7.75 (s, 1H), 7.41 (t, J = 8.1 Hz, 1H), 7.01 (d, J =8.1 Hz, 1H), 6.55 (s, 1H), 2.18 (s, 6H); 19F NMR (282 MHz, DMSO-d6):−57.01, −163.96; LCMS: pu 326 5-Fluoro-N2- (indol-6-yl)-N4-(3-trifluoromethoxyphenyl)-2,4- ¹H NMR (DMSO-d6): d 10.83 (bs, 1H), 9.49(s, 1H), 9.11 (s, 1H), 8.13 + + pyrimidinediamine (dd, J = 1.2 and 3.3Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 13.2 Hz, 2H), 7.40-7.32(m, 2H), 7.21-7.16 (m, 2H), 6.99-6.95 (m, 1H), 6.34-6.28 (m, 1H); 19FNMR (282 MHz, DMSO-d6): - 327 5-Fluoro-N4-[1-(N-methylamino)carbonylindol-6-yl]-N2-[3- (N- ¹H NMR (DMSO-d6): d 10.87(bs, 1H), 9.61 (s, 1H), 9.46-9.43 (m, 1H), +methylamino)carbonylmethyleneoxyphenyl]-2,4- 8.08 (d, J = 3.6 Hz, 1H),8.04-7.98 (m, 1H), 7.40-7.25 (m, 4H), 7.02 pyrimidinediamine (dd, J =1.8 and 8.4 Hz, 1H), 6.95-6.90 (m, 1H), 6.77-6.70 (m, 2H), 6.38-6.35 (m,1H), 4.39 (s, 2H), 2.62 (d, J = 4.8 Hz 328 N2- (3,5-Dimethoxyphenyl)-N4-(3,5-dimethylphenyl)-5-fluoro- ¹H NMR (DMSO-d6): d 9.15 (bs, 1H), 9.11(s, 1H), 8.07 (d, J = 3.9 Hz, + 2,4-pyrimidinediamine 1H), 7.37 (s, 2H),6.89 (d, J = 1.81 Hz, 2H), 6.68 (s, 1H), 6.05 (t, J = 2.1 Hz, 1H), 3.61(s, 6H), 2.23 (s, 6H); 19F NMR (282 MHz, DMSO-d6): −163.60; LCMS:purity: 99%; MS (m/e): 369 (MH 329 N4- (3,5-Dimethylphenyl)-5-fluoro-N2-(3-methoxy-5- ¹H NMR (DMSO-d6): d 9.45 (s, 1H), 9.22 (s, 1H), 8.12 (d, J= 3.9 Hz, + trifluoromethylphenyl)-2,4-pyrimidinediamine 1H), 7.68-7.64(m, 1H), 7.58-7.54 (m, 1H), 7.33 (s, 2H), 6.71 (s, 2H), 3.69 (s, 3H),2.23 (s, 6H); LCMS: purity: 99%; MS (m/e): 407 (MH+). 330 N4-(3,5-Dimethylphenyl)-5-fluoro-N4- (3-methyl-5- ¹H NMR (DMSO-d6): d 10.11(bs, 1H), 9.94 (bs, 1H), 8.25 (d, J = 4.8 +trifluoromethylphenyl)-2,4-pyrimidinediamine Hz, 1H), 7.67 (s, 2H), 7.24(s, 2H), 7.14 (s, 1H), 6.80 (s, 1H), 2.25 (s, 3H), 2.21 (s, 6H); 19F NMR(282 MHz, DMSO-d6): −61.76, −161.10; LCMS: purity: 99%; MS (m/e): 390(M+). 331 N2- (3,5-Dimethylphenyl)-5-fluoro-N4- (3-methoxy-5- ¹H NMR(DMSO-d6): d 9.86 (bs, 1H), 9.42 (bs, 1H), 8.20 (d, J = 4.2 Hz, +trifluoromethylphenyl)-2,4-pyrimidinediamine 1H), 7.80-7.76 (m, 1H),7.56-7.51 (m, 1H), 7.18 (s, 2H), 6.94 (s, 1H), 6.59 (s, 1H), 3.74 (s,3H), 2.15 (s, 6H); LCMS: purity: 97%; MS (m/e): 407 (MH+). 332 N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4- (3-methoxy-5- ¹H NMR (DMSO-d6): d9.59 (bs, 1H), 9.24 (bs, 1H), 8.18 (d, J = 3.3 Hz, +trifluoromethylphenyl)-2,4-pyrimidinediamine 1H), 7.84-7.68 (m, 1H),7.61-7.57 (m, 1H), 6.89 (d, J = 2.4 Hz, 3H), 6.06 (t, J = 2.4 Hz, 1H),3.77 (s, 3H), 3.61 (s, 6H); 19F NMR (282 MHz, DMSO-d6): −61.85, −163.20;LCMS: purity: 97%; 333 N2,N4-Bis(3-methoxy-5-trifluoromethylphenyl)-5-fluoro-2,4- ¹H NMR (DMSO-d6): d9.80 (bs, 1H), 9.72 (s, 1H), 8.25 (d, J = 3.3 Hz, + pyrimidinediamine1H), 7.77-7.72 (m, 1H), 7.60-7.52 (m, 3H), 6.92 (s, 1H), 6.75 (s, 1H),3.77 (s, 3H), 3.71 (s, 3H); 19F NMR (282 MHz, DMSO-d6): −61.90, −161.82;LCMS: purity: 97%; MS (m/e): 477 (MH+). 334 5-Fluoro-N4-(3-methoxy-5-trifluoromethylphenyl)-N2- (3- ¹H NMR (DMSO-d6): d 9.83(bs, 1H), 9.72 (bs, 1H), 8.25 (d, J = 3.6 Hz, +methyl-5-trifluoromethylphenyl)-2,4-pyrimidinediamine 1H), 7.81-7.68 (m,3H), 7.57-7.52 (m, 1H), 7.06 (s, 1H), 6.96-6.91 (m, 1H), 3.75 (s, 3H),2.26 (s, 3H); 19F NMR (282 MHz, DMSO-d6): −61.82, −162.02; LCMS: purity:91%; MS (m/e): 461 (M 335 5-Fluoro-N4-(3-methoxy-5-trifluoromethylphenyl)-N2- (3,4,5- ¹H NMR (DMSO-d6): d 9.67(bs, 1H), 9.24 (bs, 1H), 8.17 (d, J = 3.6 Hz, +trimethoxyphenyl)-2,4-pyrimidinediamine 1H), 7.84-7.78 (m, 1H), 7.59 (s,1H), 6.95-6.87 (m, 3H), 3.74 (s, 3H), 3.59 (s, 6H); 19F NMR (282 MHz,DMSO-d6): −61.86, −163.40; LCMS: purity: 96%; MS (m/e): 469 (MH+). 336N2- (3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4- (3- ¹H NMR(DMSO-d6): d 9.56 (s, 1H), 9.09 (s, 1H), 8.61 (s, 1H), 8.14 (d, +methoxy-5-trifluoromethylphenyl)-2,4-pyrimidinediamine J = 3.6 Hz, 1H),7.82-7.77 (m, 1H), 7.57-7.53 (m, 1H), 7.52-7.48 (m, 1H), 7.27-7.23 (m,1H), 6.89 (bs, 1H), 3.76 (s, 3H), 2.10 (s, 3H); 19F NMR (282 MHz,DMSO-d6): −61.80, −164.13; LCM 337 N2- (3,5-Dichlorophenyl)-5-fluoro-N4-(3-methoxy-5- ¹H NMR (DMSO-d6): d 9.74 (s, 1H), 9.70 (s, 1H), 8.25 (d, J= 3.6 Hz, + trifluoromethylphenyl)-2,4-pyrimidinediamine 1H), 7.77-7.71(m, 3H), 7.55-7.50 (m, 1H), 7.03-7.01 (m, 1H), 6.95- 6.93 (m, 1H), 3.79(s, 3H); 19F NMR (282 MHz, DMSO-d6): −61.78, −161.76; LCMS: purity: 96%;MS (m/e): 448 (MH+). 338 N2-[3,5-Bis(hydroxymethylene)phenyl]-5-fluoro-N4- (3- ¹H NMR (DMSO-d6): d 10.11(bs, 1H), 9.82 (bs, 1H), 8.26 (d, J = 4.2 + +methoxy-5-trifluoromethylphenyl)-2,4-pyrimidinediamine Hz, 1H),7.83-7.79 (m, 1H), 7.57-7.51 (m, 1H), 7.34 (bs, 2H), 6.99-6.94 (m, 2H),4.38 (s, 4H), 3.74 (s, 3H); LCMS: purity: 92%; MS (m/e): 439 (MH+). 339N2- (4-Chloro-3,5-dimethylphenyl)-5-fluoro-N4- (3-methoxy-5- ¹H NMR(DMSO-d6): d 9.98 (bs, 1H), 9.66 (bs, 1H), 8.24 (d, J = 4.2 Hz, −trifluoromethylphenyl)-2,4-pyrimidinediamine 1H), 7.76-7.71 (m, 1H),7.56-7.52 (m, 1H), 7.37 (s, 2H), 6.98-6.95 (m, 1H), 3.75 (s, 3H), 2.20(s, 6H); LCMS: purity: 98%; MS (m/e): 442 (MH+). 340 N2,N4-Bis(3,5-dimethoxyphenyl)-5-fluoro-2,4- 1H NMR (DMSO-d6): d 9.27 (s, 1H),9.18 (s, 1H), 8.10 (d, 1H, J = 3.9 + + pyrimidinediamine Hz), 6.99 (d,2H, J = 2.1 Hz), 6.92 (d, 2H, J = 2.4 Hz), 6.21 (t, 1H, J = 2.1 Hz),6.05 (t, 1H, J = 2.4 Hz), 3.68 (s, 6H), 3.62 (s, 6H); LCMS: purity:100%; MS (m/e): 401 (MH+) 341 N2,N4-Bis(3,5-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine ¹H NMR (DMSO-d6): d9.11 (s, 1H), 8.98 (s, 1H), 8.05 (d, 1H, J = 3.9 + Hz), 7.33 (bs, 2H),7.24 (bd, 2H), 6.69 (bs, 1H), 6.51 (bs, 1H), 2.25 (bs, 6H), 2.14 (s,6H); LCMS: purity: 100%; MS (m/e): 336 (M+). 342 N2-[3,5-Bis(hydroxymethylene)phenyl]-N4- (3,4- ¹H NMR (DMSO-d6): d 9.10 (s, 1H),9.09 (s, 1H), 8.02 (d, 1H, J = 3.9 +ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine Hz), 7.44 (s, 2H),7.28 (d, 1H, J = 3.0 Hz), 7.24 (d, 1H, J = 2.7 Hz), 6.86 (s, 1H), 6.79(d, 1H, J = 8.7 Hz), 5.05 (t, 2H, J = 6 Hz), 4.39 (d, 4H, J = 5.4 Hz),4.22 (bs, 4H); LCMS: purity: 97 343 N2-[3,5-Bis(hydroxymethylene)phenyl]-N4- (3,5- 1H NMR (DMSO-d6): d 9.19 (s, 1H),9.15 (s, 1H), 8.08 (d, 1H, J = 3.6 + +dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine Hz), 7.46 (s, 2H), 7.01(d, 2H, J = 2.1 Hz), 6.86 (s, 1H), 6.21 (t, 1H, J = 1.8 Hz), 5.03 (t,2H, J = 5.4 Hz), 4.38 (d, 4H, J = 5.4 Hz), 3.68 (s, 6H); LCMS: purity:86%; MS (m/e): 401 (MH+ 344 N2-[3,5-Bis (hydoxymethylene)phenyl]-N4-(2,2-dimethyl-3-oxo- ¹H NMR (DMSO-d6): d 10.55 (s, 1H), 9.27 (bd, 1H),8.97 (s, 1H), 8.04 + +4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine (d, 1H, 3.6 Hz),7.44 (d, 2H, J = 1.2 Hz), 7.39 (dd, 1H, J = 2.4 and 8.4 Hz), 7.24 (d,1H, J = 2.4 Hz), 6.88 (d, 1H, J = 8.7 Hz), 6.85 (bs, 1H), 6.38 (s, 2H),5.08 (t, 1H, J = 5.6 Hz), 4.93 (t 345 N2-[3,5-Bis(hydroxymethylene)phenyl]-N4- (3-chloro-4- ¹H NMR (DMSO-d6): d 9.26 (s,1H), 9.15 (s, 1H), 8.07 (bd, 1H, J = 3.9 +methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine Hz), 7.79 (dd, 1H, J = 2.7and 9 Hz), 7.74 (d, 1H, J = 2.7 Hz), 7.43 (s, 2H), 7.11 (d, 1H, J = 9Hz), 6.86 (s, 1H), 5.06 (t, 2H, J = 5.4 Hz), 4.38 (d, 4H, J = 5.4 Hz),3.84 (s, 3H); LCMS: puri 346 N2-[3,5-Bis (hydroxymethylene)phenyl]-N4-(3,4- ¹H NMR (DMSO-d6): d 9.50 (bs, 1H), 9.28 (s, 1H), 8.16 (d, 1H, J =3.6 + dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine Hz), 8.05 (d, 1H, J= 2.7 Hz), 7.93 (dd, 1H, J = 2.7 and 9.0 Hz), 7.52 (d, 1H, J = 8.7 Hz),7.44 (s, 2H), 6.87 (s, 1H), 5.09 (t, 2H, J = 5.7 Hz), 4.41 (d, 4H), J =5.4 Hz); LCMS: purity: 97%; 347 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[1- (N- ¹H NMR(DMSO-d6): d 11.02 (s, 1H), 10.49 (s, 1H), 9.69 (d, 1H, J = +methylaminocarbony)lindol-6-yl)-5-fluoro-2,4- 4.8 Hz), 9.53 (s, 1H),8.12 (d, 1H, J = 3.6 Hz), 7.52 (d, 1H, J = 8.4 Hz), pyrimidinediamine7.38 (t, 1H, J = 2.7 Hz), 7.11 (s, 1H), 6.81 (d, 1H, J = 2.4 Hz), 6.72(dd, 1H, J = 1.8 and 8.4 Hz), 6.59 (dd, 1H, J = 2 348 N2-(1-Aminocarbonylindol-6-yl)-N4- (2,2-dimethyl-3-oxo-4H- 1H NMR(DMSO-d6): d 11.01 (s, 1H), 10.44 (s, 1H), 9.50 (s, 1H), 8.16 −benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine (d, 1H, J = 3.6Hz), 8.07 (d, 1H, J = 5.4 Hz), 7.52 (d, 1H, J = 8.4 Hz), 7.38 (t, 1H, J= 2.7 Hz), 6.73 (dd, 1H, J = 1.5 and 8.4 Hz), 6.54 (m, 2H), 5.69 (d, 1H,J = 8.7 Hz), 2.93 (s, 2H), 1.29 (s, 6H); LCMS: purity: 95%; MS (m/e):462 (MH+) 349 N2- (4-Chloro-3,5-dimethylphenyl)-N4-(3,5-dimethoxyphenyl)- ¹H NMR (DMSO-d6): d 9.26 (bs, 1H), 9.20 (s, 1H),8.10 (d, 1H, J = 3.9 + 5-fluoro-2,4-pyrimidinediamine Hz), 7.48 (s, 2H),6.94 (d, 2H, J = 2.4 Hz), 6.23 (t, 1H, J = 2.4 Hz), 3.68 (s, 6H), 2.20(s, 6H); LCMS: purity: 92%; MS (m/e): 403 (MH+). 350 N4-(3,5-Dimethoxyphenyl)-N2- (3,5-dimethylphenyl)-5-fluoro- ¹H NMR(DMSO-d6): d 9.20 (s, 1H), 9.05 (s, 1H), 8.08 (d, 1H, J = 3.6 + + − +2,4-pyrimidinediamine Hz), 7.27 (s, 2H), 6.97 (d, 2H, J = 2.1 Hz), 6.51(s, 1H), 6.21 (t, 1H, J = 1.8 Hz), 3.67 (s, 6H), 2.15 (s, 6H); LCMS:purity: 96%; MS (m/e): 369 (MH+). 351 N4- (3,5-Dimethoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5- ¹H NMR (DMSO-d6): d 9.16 (s, 1H), 9.96 (s,1H), 8.05 (d, 1H, J = 3.3 + fluoro-2,4-pyrimidinediamine Hz), 7.22 (d,1H, J = 2.7 Hz), 7.06 (dd, 1H, J = 2.4 and 8.7 Hz), 6.99 (d, 2H, J = 2.1Hz), 6.65 (d, 1H, J = 8.7 Hz), 6.20 (t, 1H, J = 2.1 Hz), 4.17 (s, 4H),3.69 (s, 6H); LCMS: purity: 91%; M 352 N2- (3,5-Dichlorophenyl)-N4-(3,5-dimethoxyphenyl)-5-fluoro- ¹H NMR (DMSO-d6): d 9.82 (bs, 1H), 9.58(bs, 1H), 8.21 (d, 1H, J = + 2,4-pyrimidinediamine 3.6 Hz), 7.75 (bs,2H), 7.04 (t, 1H, J = 1.8 Hz), 6.89 (d, 2H, J = 1.8 Hz), 6.27 (t, 1H, J= 2.1 Hz), 3.67 (s, 6H); LCMS: purity: 95%; MS (m/e): 410 (MH+). 353 N4-(3,5-Dimethoxyphenyl)-5-fluoro-N2- (3-methyl-5- ¹H NMR (DMSO-d6): d 9.47(s, 1H), 9.31 (s, 1H), 8.15 (d, 1H, J = 3.6 +trifluoromethylphenyl)-2,4-pyrimidinediamine Hz), 7.86 (s, 1H), 7.79 (s,1H), 6.98 (m, 3H), 6.23 (t, 1H, J = 2.4 Hz), 3.68 (s, 6H), 2.27 (s, 3H);LCMS: putity: 96%; MS (m/e): 423 (MH+). 354 N2- (3,5-Dichlorophenyl)-N4-(3,4-ethylenedioxyphenyl)-5- ¹H NMR (DMSO-d6): d 9.56 (s, 1H), 9.28 (s,1H), 8.11 (d, 1H, J = 3.6 + fluoro-2,4-pyrimidinediamine Hz), 7.76 (d,2H, J = 1.8 Hz), 7.18 (d, 1H, J = 2.4 Hz), 7.13 (dd, 1H, J = 3.6 and 9Hz), 6.98 (t, 1H, J = 1.8 Hz), 6.82 (d, 1H, J = 8.7 Hz), 4.21 (bs, 4H);LCMS: purity: 81%; MS (m/e): 407 (M 355 N4-(3,5-Dimethoxyphenyl)-5-fluoro-N2- (3-methoxy-5- ¹H NMR (DMSO-d6): d9.53 (s, 1H), 9.33 (d, 1H, J = 1.5 Hz), 8.16 (d, +trifluoromethylphenyl)-2,4-pyrimidinediamine 1H, J = 3.6 Hz), 7.65 (d,1H, J = 2.1 Hz), 6.98 (d, 2H, J = 2.1 Hz), 6.72 (bs, 1H), 6.22 (t, 1H, J= 2.4 Hz), 3.72 (s, 3H), 3.69 (s, 6H); LCMS: purity: 96%; MS (m/e): 439(MH+). 356 N4- (3,4-Ethylenedioxyphenyl)-5-fluoro-N2- (3-methoxy-5- ¹HNMR (DMSO-d6): d 9.47 (s, 1H), 9.23 (s, 1H), 8.09 (d, 1H, J = 3.9 +trifluoromethylphenyl)-2,4-pyrimidinediamine Hz), 7.67 (s, 1H), 7.59 (s,1H), 7.27 (d, 1H, J = 2.7 Hz), 7.18 (dd, 1H, J = 2.4 and 8.4 Hz), 6.78(d, 1H, J = 8.7 Hz), 6.78 (s, 1H), 4.21, bs, 4H), 3.72 (s, 3H); LCMS:purity: 90%; MS (m/e) 357 N2- (3,5-Dimethoxyphenyl)-5-fluoro-N4-[3,4- ¹HNMR (DMSO-d6): d 9.64 (s, 1H), 9.29 (s, 1H), 8.15 (m, 2H), 7.62 + +(tetrafluoroethylenedioxy)phenyl]-2,4-pyrimidinediamine (dd, 1H, J = 2.4and 9 Hz), 7.39 (d, 1H, J = 8.7 Hz), 6.90 (d, 2H, J = 2.4 Hz), 6.09 (t,1H, J = 1.8 Hz), 3.66 (s, 6H); LCMS: purity: 97%; MS (m/e): 471 (MH+)358 N2- (4-Chloro-3,5-dimethylphenyl)-5-fluoro-N4-[3,4- ¹H NMR(DMSO-d6): d 9.90 (bs, 1H), 9.56 (bs, 1H), 8.21 (bd, 1H, J = −(tetrafluoroethylenedioxy)phenyl]-2,4-pyrimidinediamine 3.6 Hz), 8.06(bs, 1H), 7.57 (dd, 1H, J = 2.4 and 9.0 Hz), 7.43 (d, 1H, J = 9.3 Hz),7.39 (s, 2H), 7.06 (bs, 1H), .25 (s, 6H); LCMS: purity: 97%; MS (m/e):473 (MH+). 359 N2-[3,5-Bis (hydroxymethylene)phenyl]-5-fluoro-N4-[3,4-¹H NMR (DMSO-d6): d 9.60 (s, 1H), 9.32 (s, 1H), 8.16 (d, 2H, J = 3.6 +(tetrafluoroethylenedioxy)phenyl]-2,4-pyrimidinediamine Hz), 7.70 (dd,1H, J = 2.7 and 9 Hz), 7.47 (s, 2H), 7.40 (d, 1H, J = 9.0 Hz), 6.88 (bs,1H), 5.11 (t, 2H, J = 5.4 Hz), 4.42 (d, 4H, J = 5.4 Hz); LCMS: purity:98%; MS (m/e): 471 (MH+). 360 N2- (3,5-Dichlorophenyl)-5-fluoro-N4-[3,4-¹H NMR (DMSO-d6): d 9.76 (s, 1H), 9.72 (s, 1H), 8.25 (d, 1H, J = 3.6 −(tetrafluoroethylenedioxy)phenyl]-2,4-pyrimidinediamine Hz), 8.00 (d,1H, J = 2.4 Hz), 7.74 (d, 2H, J = 1.8 Hz), 7.58 (dd, 1H, J = 2.4 and 9.0Hz), 7.44 (d, 1H, J = 9.0 Hz), 7.04 (t, 1H, J = 1.8 Hz); LCMS: purity:98%; MS (m/e): 480 (MH+). 361 5-Fluoro-N2-(3-methoxy-5-trifluoromethylphenyl)-N4-[3,4- ¹H NMR (DMSO-d6): d 9.72(s, 1H), 9.64 (s, 1H), 8.23 (d, 1H, J = 3.6 +(tetrafluoroethylenedioxy)phenyl]-2,4-pyrimidinediamine Hz), 8.07 (d,1H, J = 2.4 Hz), 7.67 (bs, 1H), 7.60 (dd, 1H, J = 2.4 and 9.3 Hz), 7.54(bs, 1H), 7.39 (d, 1H, J = 9 Hz), 6.75 (bs, 1H), 3.75 (s, 3H); LCMS:purity: 97%: MS (m/e): 509 (MH+) 362 N2-(3,5-Dimethyphenyl)-5-fluoro-N4-[3,4- ¹H NMR (DMSO-d6): d 9.60 (s, 1H),9.19 (s, 1H), 8.15 (d, 1H, J = 3.6 + −(tetrafluoroethylenedioxy)phenyl]-2,4-pyrimidinediamine Hz), 8.12 (d,1H, J = 2.4 Hz), 7.60 (dd, 2.4 and 8.7 Hz), 7.40 (d, 1H, J = 9 Hz), 7.22(s, 2H), 6.56 (s, 1H), 2.18 (s, 6H); LCMS: purity: 100%; MS (m/e): 439(MH+). 363 N4- (3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3,4- ¹H NMR(DMSO-d6): d 9.53 (s, 1H), 9.27 (s, 1H), 8.08 (d, 1H, J = 3.6 +(tetrafluoroethylenedioxy)phenyl]-2,4-pyrimidinediamine Hz), 7.93 (d,1H, J = 2.4 Hz), 7.37 (dd, 1H, J = 2.4 and 9.3 Hz), 7.26 (d, 1H, J = 9Hz), 7.11 (dd, 1H, J = 2.4 and 8.7 Hz), 6.80 (d, 1H, J = 8.4 Hz), 4.22(s, 4H); LCMS: purity: 96%; MS (m/e) 364 N4-(3,5-Dimethoxyphenyl)-5-fluoro-N2-[3,4- ¹H NMR (DMSO-d6): d 9.59 (s,1H), 9.37 (d, 1H, J = 0.9 Hz), 8.14 (d, +(tetrafluoroethylenedioxy)phenyl]-2,4-pyrimidinediamine 1H, J = 2.4 Hz),7.38 (dd, 1H, J = 2.7 and 9.3 Hz), 7.27 (d, 1H, J = 9.0 Hz), 6.91 (d,2H, J = 2.4 Hz), 6.26 (t, 1H, J = 2.4 Hz), 3.69 (s, 6H); LCMS: purity:96%; MS (m/e): 471 (MH+). 365 5-Fluoro-N2-[2-(N-methylamino)carbonylindol-7-yl]-N4-[3,4- ¹H NMR (DMSO-d6): d 11.59(s, 1H), 9.66 (s, 1H), 9.34 (s, 1H), 8.46 +(tetrafluoroethylenedioxy)phenyl]-2,4-pyrimidinediamine (d, 1H, J = 4.8Hz), 8.20 (d, 1H, J = 3.6 Hz), 8.10 (d, 1H, J = 2.4 Hz), 7.91 (d, 1H, J= 7.2 Hz), 7.60 (dd, 1H, J = 2.7 and 9 Hz), 7.39 (d, 1H, J = 9.0 Hz),7.24 (d, 1H, J = 7.5 Hz), 7.06 (d, 1 366 5-Fluoro-N2-(3-methyl-5-trifluoromethyl)-N4-[3,4- ¹H NMR (DMSO-d6): d 9.70 (s, 1H),9.60 (s, 1H), 8.22 (d, 1H, J = 2.4 +(tetrafluoroethylenedioxy)phenyl]-2,4-pyrimidinediamine Hz), 8.07 (d,1H, J = 2.4 Hz), 7.87 (s, 1H), 7.70 (s, 1H), 7.60 (dd, 1H, J = 2.1 and 9Hz), 7.41 (d, 1H, J = 9 Hz), 7.04 (s, 1H), 2.31 (s, 3H); LCMS: purity:100%; MS (m/e): 493 (MH+). 367 N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[3,4- ¹H NMR (DMSO-d6): d 9.48 (s,1H), 9.12 (s, 1H), 8.11 (d, 2H, J = 3.6 + +(tetrafluoroethylenedioxy)phenyl]-2,4-pyrimidinediamine Hz), 7.59 (dd,1H, J = 2.4 and 9 Hz), 7.39 (d, 1H, J = 9.3 Hz), 7.22 (d, 1H, J = 2.4Hz), 6.99 (dd, 1H, J = 2.4 and 8.7 Hz), 6.70 (d, 1H, J = 9 Hz); LCMS:purity: 96%; MS (m/e): 469 (MH+). 368 N4-(3,5-Dimethoxyphenyl)-5-fluoro-N2-[2- (N- ¹H NMR (DMSO-d6): d 11.70 (s,1H), 9.31 (s, 1H), 9. 28 (s, 1H), 8.43 + +methylamino)carbonylindol-7-yl]-2,4-pyrimidinediamine (d, 1H, J = 4.8Hz), 8.14 (d, 1H, J = 4.8 Hz), 8.04 (dd, 1H, J = 0.9 and 8.4 Hz), 7.19(d, 1H, J = 7.5 Hz), 7.03 (d, 1H, J = 2H, J = 2.4 Hz), 6.89 (t, 1H, J =8.4 Hz), 6.24 (t, 1H, J = 2.4 Hz), 369 N2-(3-Chloro-5-methoxyphenyl)-N4- (2,2-dimethyl-3-oxo-4H- ¹H NMR (DMSO-d6):d 10.57 (s, 1H), 9.35 (s, 1H), 9.27 (s, 1H), 8.10 +benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine (d, 1H, J = 3.6Hz), 7.47 (m, 1H), 7.25 (dd, 1H, J = 2.7 and 8.7 Hz), 7.16 (d, 2H, J =2.1 Hz), 6.87 (d, 1H, J = 8.4 Hz), 6.49 (t, 1H, J = 1.8 Hz), 3.66 (s,3H), 1.40 (s, 6H); LCMS: purity: 10 370 N2-(3-Chloro-5-methoxyphenyl)-N4- (3,4-ethylenedioxyphenyl)- ¹H NMR(DMSO-d6): d 9.31 (s, 1H), 9.21 (s, 1H), 8.08 (d, 1H, J = 3.9 +5-fluoro-2,4-pyrimidinediamine Hz), 7.48 (t, 1H, J = 1.8 Hz), 7.20 (m,3H), 6.80 (d, 1H, J = 8.4 Hz), 6.49 (t, 1H, J = 2.4 Hz), 4.21 (s, 4H),3.67 (s, 3H); LCMS: purity: 95%; MS (m/e): 403 (MH+). 371 5-Fluoro-N4-(3,4-methylenedioxyphenyl)-N2-[2- (N- ¹H NMR (DMSO-d6): d 11.27 (s, 1H),9.25 (s, 2H), 8.43 (d, 1H, J = 4.5 +methylamino)carbonylindol-7-yl]-2,4-pyrimidinediamine Hz), 8.09 (d, 1H,J = 3.9 Hz), 8.01 (d, 1H, J = 7.8 Hz), 7.51 (d, 1H, J = 2.1 Hz), 7.6 (m,2H), 7.04 (d, 1H, J = 1.8 Hz), 6.92 (t, 1H, J = 7.8 Hz), 6.84 (d, 1H, J= 8.1 Hz), 6.01 (s, 2H), 2.81 372 N2- (3,5-Dimethoxyphenyl)-5-fluoro-N4-(3,4- ¹H NMR (DMSO-d6): d 9.20 (s, 1H), 9.10 (s, 1H), 8.05 (d, 1H, J =3.6 + methylenedioxyphenyl)-2,4-pyrimidinediamine Hz), 7.44 (d, 1H, J =2.1 Hz), 7.16 (dd, 1H, J = 2.1 and 8.4 Hz), 6.93 (d, 2H, J = 2.4 Hz),6.84 (d, 1H, J = 8.4 Hz), 6.04 (t, 1H, J = 2.1 Hz), 5.99 (s, 2H), 3.64(s, 6H); LCMS: purity: 89%; M 373 5-Fluoro-N4-(3,4-methylenedioxyphenyl)-N2- (3-methoxy-5- ¹H NMR (DMSO-d6): d 9.49(s, 1H), 9.30 (s, 1H), 8.10 (d, 1H, J = 3.6 +trifluoromethylphenyl)-2,4-pyrimidinediamine Hz), 9.67 (bs, 1H), 7.58(bs, 1H), 7.40 (d, 1H, J = 1.8 Hz), 7.11 (dd, 1H, J = 1.8 and 8.4 Hz),6.84 (d, 1H, J = 8.4 Hz), 6.70 (bs, 1H), 6.99 (s, 2H), 3.73 (s, 3H);LCMS: purity: 97%; MS (m/ 374 5-Fluoro-N4-(3,4-methylenedioxyphenyl)-N2- (3-methyl-5- ¹H NMR (DMSO-d6): d 9.46 (s,1H), 9.29 (s, 1H), 8.10 (d, 1H, J = 3.6 −trifluoromethylphenyl)-2,4-pyrimidinediamine Hz), 7.78 (bs, 1H), 7.39(d, 1H, J = 2.1 Hz), 7.10 (1H, J = 2.4 and 8.4 Hz), 6.99 (bs, 1H), 6.85(d, 1H, J = 8.4 Hz), 5.99 (s, 2H), 2.28 (s, 3H); LCMS: purity: 99%; MS(m/e): 407 (MH+). 375 N2- (3,5-Dichlorophenyl)-5-fluoro-N4- (3,4- ¹H NMR(DMSO-d6): d 9.59 (s, 1H), 9.36 (s, 1H), 8.12 (d, 1H, J = 3.9 +methylenedioxyphenyl)-2,4-pyrimidinediamine Hz), 7.74 (d, 2H, J = 2.1Hz), 7.30 (d, 1H, J = 2.1 Hz), 7.06 (dd, 1H, J = 2.4 and 8.4 Hz), 6.97(t, 1H, 2.1 Hz), 6.88 (d, 1H, J = 8.4 Hz); 6.00 (s, 2H); LCMS: purity:94%; MS (m/e): 393 (M+ 376 N2- (3,5-Dimethylphenyl)-5-fluoro-N4- (3,4-¹H NMR (DMSO-d6): d 9.18 (bs, 1H), 9.03 (s, 1H), 8.04 (d, 1H, J = 3.9 +methylenedioxyphenyl)-2,4-pyrimidinediamine Hz), 7.43 (d, 1H, J = 2.1Hz), 7.24 (s, 2H), 7.11 (dd, 1H, J = 2.1 and 8.4 Hz), 6.85 (d, 1H, J =8.4 Hz), 6.50 (bs, 1H), 5.98 (s, 2H), 2.16 (s, 6H); LCMS: purity: 87%;MS (m/e): 353 (MH+). 377 N2- (4-Chloro-2,5-dimethoxyphenyl)-N4-(3-chloro-4- LCMS: purity: 100%; MS (m/e): 439 (M+). +methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 378 N2-(3-Chloro-4-methoxyphenyl)-N4- (2,2-dimethyl-3-oxo-4H- ¹H NMR (DMSO-d6):d 10.63 (s, 1H), 10.05 (s, 1H), 9.62 (s, 1H), 8.15 +benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine p- (d, 1H, J = 4.8Hz), 7.66 (bs, 1H), 7.44 (dd, 2H, J = 1.8 and 8.7 Hz), Toluene SulfonicAcid Salt 7.35 (bd, 1H, J = 9 Hz), 7.20 (dd, 1H, J = 2.1 and 8.7 Hz),7.10 (bd, 2H, J = 7.5 Hz), 7.02 (d, 1H, J = 9 Hz), 6.89 (d, 1 379 N2-(4-Chloro-2,5-dimethoxyphenyl)-N4- (3,4- ¹H NMR (DMSO-d6): d 9.24 (s,1H), 8.05 (d, 1H, J = 3.9 Hz), 7.87 (s, +ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 1H), 7.70 (s, 1H),7.17 (d, 1H, J = 2.4 Hz), 7.06 (m, 2H), 6.74 (d, 1H, J = 8.7 Hz), 4.21(s, 4H), 3.79 (s, 3H), 3.54 (s, 3H); LCMS: purity: 100%; MS (m/e): 433(MH+). 380 N2- (4-Chloro-2,5-dimethoxyphenyl)-N4- (3,5- LCMS: purity:100%; MS (m/e): 435 (MH+). +dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 381 N4-(3,5-Dimethoxyphenyl)-5-fluoro-N2- (2- ¹H NMR (DMSO-d6): d 9.36 (s, 1H),8.25 (d, 1H, J = 1.8 Hz), 8.11 (d, + +methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine 1H, J = 3.9 Hz),7.57 (m, 3H), 6.99 (m, 2H), 6.26 (t, 1H, J = 2.1 Hz), 3.88 (s, 3H), 3.69(s, 6H); LCMS: purity: 92%; MS (m/e): 439 (MH+). 382 N2-(2-Carboxybenzofuran-5-yl)-N4- (3,5-dimethoxyphenyl)-5- LCMS: purity:91%; MS (m/e): 425 (MH+). − − fluoro-2,4-pyrimidinediamine 383 N2-(2-Carboxyindol-7-yl)-N4- (3,5-dimethoxyphenyl)-5-fluoro- 1H NMR(DMSO-d6): d 11.85 (s, 1H), 9.31 (s, 1H), 9.26 (s, 1H), 8.16 +2,4-pyrimidinediamine (d, 1H, J = 3.6 Hz), 8.12 (d, 1H, J = 8.1 Hz),7.22 (d, 1H, J = 8.1 Hz), 7.02 (d, 2H, J = 2.1 Hz), 6.91 (t, 1H, J = 7.8Hz), 6.25 (s, 1H)3.70 (bs, 6H); LCMS: purity: 80%; MS: 424 (MH+) 384 N4-(3,5-Dimethoxyphenyl)-5-fluoro-N2-[2- (N-2-hydroxyethyl-N- ¹H NMR(DMSO-d6): d 11.52 (s, 1H), 9.30 (bs, 1H), 9.27 (s, 1H), 8.14 + + +methylamino)carbonylindol-7-yl]-2,4-pyrimidinediamine (d, 1H, J = 3.6Hz), 8.04 (m, 1H), 7.22 (d, 1H, J = 8.4 Hz), 7.03 (m, 2H), 6.90 9m, 2H),6.23 9bs, 1H), 3.68 (s, 6H), 3.64 (bs, 4H), 3.20 (s, 3H); LCMS: purity:94%; MS (m/e): 481 (MH+). 385 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-methyl-N2-[3- (N- 1H NMR (CDCl3):d 7.50 (bs, 1H), 7.30 (m, 2H), 6.91 (bd, 1H, J = 7.2 + + −methylamino)carbonylmethyleneoxyphenyl]-2,4- Hz), 6.73 (m, 5H), 4.49 (s,2H), 4.31 (s, 4H), 3.60 (s, 3H), 2.92 (d, 3H, pyrimidinediamine J = 4.5Hz); : CMS: purity: 97%, MS (m/e): 440 (MH+) 386 N4-(3,4-Ethylenedioxyphenyl)-N2- (3,5-dimethoxyphenyl)-5- 1H NMR (CDCl3): d7.94 (d, 1H, J = 5.1 Hz), 7.50 (bd, 1H), 6.90 (d, + + −fluoro-N4-methyl-2,4-pyrimidinediamine 1H, J = 9 Hz), 6.83 (s, 1H), 6.73(m, 3H), 6.62 (d. 1H, 2.4 Hz), 4.31 (m, 4H), 3.80 (s, 3H), 3.79 (s, 3H),3.60 (s, 3H); LCMS: purity: 90%, MS: 413 (MH+). 387 N2-(3,5-Dimethylphenyl)-N4- (3,4-ethylenedioxyphenyl)-5- 1H NMR (CDCl3): d7.50 (bd, 1H), 7.40 (s, 1H), 7.27 (m, 1H), 6.90 + −fluoro-N4-methyl-2,4-pyrimidinediamine (bdd, 1H), 6.81 (m, 1H), 6.77 (d,2H, J = 2.4 Hz), 6.70 (dd, 1H, J = 2.7 and 8.7 Hz), 4.30 (s, 4H), 3.50(s, 3H), 2.32 (s, 6H); LCMS: purity: 94%, MS (m/e): 381 (MH+). 388 N2-(3,5-Dimethoxyphenyl)-N4- (2,2-dimethyl-3-oxo-4H- 1H NMR (DMSO-d6): d10.60 (s, 1H), 9.21 (s, 1H), 7.94 (d, 1H, J = 6.0 − −benz[1,4]oxazin-6-yl)-5-fluoro-N4-methyl-2,4- Hz), 7.01 (d, 2H, J = 1.2Hz), 6.88 (m, 2H), 6.75 (d, 1H, J = 2.4 Hz), pyrimidinediamine 6.05 (t,1H, J = 2.4 Hz), 3.60 (s, 6H), 3.41 (s, 3H), 1.34 (s, 6H); LCMS: purity:92%, MS (m/e): 454 (MH+). 389 N4- (3,5-Dimethoxyphenyl)-N2-[2-(N-1,1-dimethyl-2- ¹H NMR (DMSO-d6): d 11.63 (s, 1H), 9.25 (d, 1H, J =7.8 Hz), 8.14 (d, + −hydroxyethylamino)carbonylindol-7-yl]-5-fluoro-2,4- 1H, J = 3.6 Hz),8.02 (d, 1H, J = 8.1 Hz), 7.53 (s, 1H), 7.19 (d, 1H, J =pyrimidinediamine 7.5 Hz), 7.14 (s, 1H), 7.04 (s, 2H), 6.89 (t, 1H, J =7.5 Hz), 6.23 (s, 1H), 4.94 (t, 1H, J = 6.3 Hz), 3.69 (s, 6H), 3902-Chloro-N4- (3,4-ethylenedioxyphenyl)-5-fluoro-N4-methyl-4- 1H NMR(CDCl3): d 7.85 (d, 1H, J = 4.8 Hz), 6.86 (d, 1H, J = 8.4 Hz), − − −pyrimidineamine 6.73 (d, 1H, J = 2.7 Hz), 6.60 (dd, 1H, J = 2.7 and 8.1Hz); LCMS: purity: 100%, MS (m/e): 296 (M+). 391 N2-(3,5-Dimethylphenyl)-5-fluoro-N4-methyl-N4- (3-oxo-2,2,4- 1H NMR(CDCl3): d 7.95 (d, 1H, J = 6.4 Hz), 7.67 (bs, 1H), 7.21 (s, + +trimethylbenz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 2H), 6.96 (s, 1H),6.87 (dd, 1H, J = 2.4 and 8.7 Hz), 6.78 (d, 1H, J = 2.4 Hz), 6.72 (s,1H), 3.55 (s, 3H), 3.32 (s, 3H), 2.30 (s, 6H), 1.53 (s, 6H); LCMS:purity: 92%, MS (m/e): 436 (MH+). 392 N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-methyl-N4- (3-oxo- 1H NMR(CD3OD): d 7.77 (d, 1H, J = 2.4 Hz), 7.75 (bd, 1H), 7.34 (dd, + +2,2,4-trimethylbenz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 1H, J = 2.7and 9.3 Hz), 7.05 (d, 1H, J = 1.8 Hz), 6.95 (m, 3H), 4.62 (s, 3H), 3.83(s, 3H), 3.51 (s, 3H), 1.48 (s, 6H); LCMS: purity: 94%, MS (m/e): 472(M+). 393 N2- (3,5-Dimethoxyphenyl)-5-fluoro-N4-methyl-N4- (3-oxo- 1HNMR (CD3OD): d 7.78 (d, 1H, J = 8.4 Hz), 7.07 (bs, 1H), 6.96 (bs, + +2,2,4-trimethylbenz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 2H), 6.87 (d,2H, J = 2.4 Hz), 6.10 (t, 1H, J = 2.4 Hz), 3.70 (s, 6H), 3.54 (s, 3H),3.32 (s, 3H), 1.48 (s, 6H); LCMS: purity: 97%, MS (m/e): 468 (MH+). 394N2- (3-Chloro-4-methoxyphenyl)-N4- (2,2-dimethyl-3-oxo-4H- LCMS: purity:93%, MS (m/e): 351 (MH+). + +benz[1,4]oxazin-6-yl)-5-fluoro-N4-methyl-2,4- pyrimidinediamine 395 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2- (2- 1H NMR (DMSO-d6): d 7.95 (s,1H), 7.76 (bd, 1H), 7.54 (s, 1H), 7.49 + + +methoxycarbonyl-benzofuran-5-yl)-N4-methyl-2,4- (bd, 2H), 6.87 (d, 1H, J= 8.4 Hz), 6.79 (dd, 1H, J = 2.4 and 6.6 Hz), pyrimidinediamine 6.74(bd, 1H); LCMS: purity: 94%, MS (m/e): 452 (MH+). 396 N2-(3,5-Dimethylphenyl)-N4- (3-oxo-2,2,4- LCMS: purity: 90%; MS (m/e): 422(MH+). + + +trimethylbenz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 397 N2-(3,5-Dimethoxyphenyl)-N4- (3-oxo-2,2,4- LCMS: purity: 94%; MS (m/e): 454(MH+). + + +trimethylbenz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 398 N4-(3,5-Dimethoxyphenyl)-5-fluoro-N4-methyl-N2-[3- (N- LCMS: purity: 94%,MS (m/e): 442 (MH+). + − methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 399 N4- (3,5-Dimethoxyphenyl)-N2-(3,5-dimethylphenyl)-5-fluoro- LCMS: purity: 92%, MS (m/e): 382(MH+). + + − + N4-methyl-2,4-pyrimidinediamine 400 N2,N4-Bis(3,5-dimethoxyphenyl)-5-fluoro-N4-methyl-2,4- 1H NMR (DMSO-d6): d 9.23(s, 1H), 7.97 (d, 1H, J = 5.1 Hz), 7.01 (d, + − pyrimidinediamine 2H, J= 1.8 Hz), 6.45 (d, 2H, J = 1.2 Hz), 6.34 (bt, 1H), 6.05 (bt, 1H), 3.72(s, 6H), 3.68 (6H), 3.45 (s, 3H); LCMS: purity: 95%, MS (m/e): 415(MH+). 401 N4- (3,5-Dimethoxyphenyl)-5-fluoro-N2- (2-methoxycarbonyl- 1HNMR (DMSO): d 9.70 (s, 1H), 8.13 (s, 1H), 8.04 (d, 1H, J = 3.8 Hz), + +benzofuran-5-yl)-N4-methyl-2,4-pyrimidinediamine 7.69 (s, 1H), 7.62 (m,2H), 6.51 (d, 2H, J = 1.5 Hz), 6.44 (bt, 1H); 3.88 (s, 3H), 3.72 (s,6H), 3.46 (s, 3H); LCMS: MS (m/e): 453 (MH+), purity: 95%. 402N4-[3-Chloro-4- (methoxycarbonyl-1,1- LCMS: purity: 81%; MS (m/e): 459(MH+) + dimethylmethyleneoxy)phenyl]-N2- (3,5-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine 403 N2- (3,5-Dimethylphenyl)-N4-[4-(methoxycarbonyl-1,1- LCMS: purity: 80%; MS (m/e): 425 (MH+). +dimethylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine 404 N2-(3-Chloro-4-methoxyphenyl)-N4- (3,5-dimethoxyphenyl)-5- 1H NMR(DMSO-d6): d 10.00 (s, 1H), 8.08 (d, 1H, J = 6.00 Hz), 7.89 − −fluoro-N4-methyl-2,4-pyrimidinediamine (d, 1H, J = 5.1 Hz), 7.47 (dd,1H, J = 2.7 and 9.3 Hz), 7.08 (d, 1H, J = 9.0 Hz), 6.53 (d, 2H, J = 1.8Hz), 6.46 (t, 1H, J = 2.1 Hz); LCMS: purity: 92%, 419 (MH+). 405 N2-(4-Chloro-3-methoxyphenyl)-N4- (3,5-dimethoxyphenyl)-5- 1H NMR(DMSO-d6): d 9.30 (s, 1H), 9.03 (s, 1H), 8.07 (d, 1H, J = 4.2 + −fluoro-N4-methyl-2,4-pyrimidinediamine Hz), 7.48 (d, 1H, J = 2.1 Hz),7.37 (dd, 1H, J = 2.4 and 8.4 Hz), 7.24 (s, 2H); LCMS: purity: 91%, MS(m/e): 419 (M+). 406 N4- (3,5-Dimethoxyphenyl)-5-fluoro-N4-methyl-N2-[2-(N- 1H NMR (DMSO-d6): d 11.71 (s, 1H), 9.39 (s, 1H), 8.44 (bd, 1H, J = +− methylamino)carbonylindol-7-yl]-2,4-pyrimidinediamine 4.8 Hz), 8.02(m, 2H), 7.20 (d, 1H, J = 7.5 Hz), 7.04 (d, 1H, J = 2.1 Hz), 6.93 (t,1H, J = 7.8 Hz), 6.47 (d, 2H, J = 2.1 Hz), 6.41 (t, 1H, J = 2.1 Hz),3.72 (s, 6H), 3.46 (s, 3H), 2.81 (d, 3H, 407 2-Chloro-N4-[3-chloro-4-(ethoxycarbonyl-1,1- 1H NMR (DMSO-d6): d 8.07 (d, 1H, J = 2.7 Hz), 7.69(m, 1H), 7.45 (m, +dimethylmethyleneoxy)phenyl]-5-fluoro-4-pyrimidineamine 1H), 6.95 (d,1H, J = 9 Hz), 6.92 (bs, 1H), 4.28 (q, 2H, J = 6.9 Hz), 1.62 (s, 6H),1.31 (t, 3H, J = 7.2 Hz); LCMS: purity: 85%; MS (m/e): 388 (M+). 408N4-[3-Chloro-4- (ethoxycarbonyl-1,1- 1H NMR (CD3OD): d 7.91 (d, 1H, J =3.6 Hz), 7.74 (d, 1H, J = 2.7 Hz), + dimethylmethyleneoxy)phenyl]-N2-(3,5-dimethoxyphenyl)-5- 7.66 (dd, 1H, J = 2.7 and 8.7 Hz), 6.91 (d, 1H,J = 9 Hz), 6.78 9d, 2H, fluoro-2,4-pyrimidinediamine J = 2.1 Hz), 6.12(t, 1H, J = 2.1 Hz), 4.26 (q, 2H, J = 6.9 Hz), 3.71 (s, 6H), 1.59 (s,6H), 1.29 (t, 3H, J = 7.2 Hz); LC 409 N4-[3-Chloro-4-(hydroxycarbonyl-1,1- 1H NMR (DMSO-d6): d 13.15 (bs, 1H), 9.38 (s, 1H),9.18 (s, 1H), 8.10 + + − dimethylmethyleneoxy)phenyl]-N2-(3,5-dimethoxyphenyl)-5- (d, 1H, J = 3.9 Hz), 7.93 (s, 1H), 7.84 (dd,1H, J = 2.7 and 9.3 Hz), 7.77 fluoro-2,4-pyrimidinediamine (d, 1H, J =2.7 Hz), 6.91 (m, 3H), 6.07 (t, 1H, J = 2.1 Hz), 3.65 (s, 6H), 1.52 (s,6H); LCMS: purity: 90%; MS (m 410 N4-[3-Chloro-4- (ethoxycarbonyl-1,1-1H NMR (DMSO-d6): d 9.36 (s, 1H), 9.17 (s, 1H), 8.08 (d, 1H, J =3.6 + + + dimethylmethyleneoxy)phenyl]-N2- (3-chloro-4- Hz), 7.78 (d,1H, J = 2.7 Hz), 7.75 (d, 1H, J = 2.1 Hz), 7.70 (dd, 1H, J =methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 3.0 and 9.3 Hz), 7.44 (dd,1H, J = 2.7 and 9.0 Hz), 6.99 (d, 1H, J = 9.0 Hz), 6.88 (d, 1H, J = 9.0Hz), 4.20 (q, 2H, 411 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-methyl-N2-[3- LCMS: purity: 91%,MS (m/e): 420 (MH+). + + − (oxazol-5-yl)phenyl]-2,4-pyrimidinediamine412 N4- (3,4-Ethylenedioxyphenyl)-5-fluoro-N4-methyl-N2-[3- 1H NMR(DMSO-d6): d 9.61 (s, 1H), 8.57 (s, 1H), 8.17 (s, 1H), 9.97 + +(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine (d, 1H, J = 6.0 Hz), 7.70(bd, 1H, J = 4.8 Hz), 7.52 (bd, 1H, J = 7.8 Hz), 7.38 (d, 1H, J = 8.1Hz), 7.33 (s, 1H), 6.79 (m, 3H), 4.24 (s, 4H), 3.44 (s, 3H); LCMS:purity: 92%, MS (m/e): 420 ( 413 N4- (3,4-Dimethoxyphenyl)-N2-(3,5-dimethylphenyl)-5-fluoro- 1H NMR (DMSO-d6): d 9.15 (s, 1H), 8.97(s, 1H), 8.02 (d, 1H, J = 3.9 + + − 2,4-pyrimidinediamine Hz), 7.24 (m,4H), 6.88 (d, 1H, J = J = 8.4 Hz), 6.48 (d, 1H), 3.73 (s, 3H), 3.65 (s,3H), 2.12 (s, 6H); LCMS: purity: 97%, MS (m/e): 369 (MH+). 414 N2-(3,5-Dimethoxyphenyl)-N4- (3,4-dimethoxyphenyl)-5-fluoro- 1H NMR(DMSO-d6): d 9.17 (s, 1H), 9.05 (s, 1H), 8.03 (d, 1H, J = 3.9 + + −2,4-pyrimidinediamine Hz), 7.32 (dd, 2.4 and 8.7 Hz), 7.24 (d, 1H, J =2.4 Hz), 6.92 (d, 2H, J = 2.4 Hz), 6.85 (d, 1H, 8.4 Hz), 6.03 (t, 1H, J= 2.1 Hz), 3.73 (s, 3H), 3.66 (s, 3H), 3.60 (s, 6H); LCMS: purity: 96415 N4- (3,4-Dimethoxyphenyl)-N2-[2- (ethoxycarbonyl)indol-7-yl]-5- 1HNMR (DMSO-d6): d 11.89 (s, 1H), 9.25 (s, 1H), 9.21 (s, 1H), 8.10 + + −fluoro-2,4-pyrimidinediamine (d, 1H, J = 3.9 Hz), 8.87 (s, 1H), 8.73 (m,3H), 7.11 (d, 1H, J = 2.1 Hz), 6.88 (m, 2H), 4.32 (q, 2H, J = 3.9 Hz),3.76 (s, 3H), 3.66 (s, 3H), 1.34 (q, t, 3H, J = 3.9 Hz); LCMS: purity:93%, 416 N4- (3,4-Ethylenedioxyphenyl)-5-fluoro-N4-methyl-N2-[4- 1H NMR(DMSO-d6): d 9.59 (s, 1H), 8.05 (s, 1H), 7.96 (d, 1H), J = 5.7 + −(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine Hz), 7.80 (bs, 4H), 7.27 (s,1H), 6.85 (m, 2H), 6.78 (dd, 1H), 4.52 (s, 4H), 3.41 (s, 3H), 3.31 (s,3H); LCMS: purity: 91%, MS (m/e): 420 (MH+). 417 2-Chloro-N4-(3,4-dimethoxyphenyl)-5-fluoro-N4-methyl-4- 1H NMR (DMSO-d6): d 8.09 (d,1H, J = 5.4 Hz), 7.02 (d, 1H, J = 2.4 − − − − pyrimidineamine Hz), 6.93(d, 1H, J = 8.4 Hz), 6.84 (dd, 1H, J = 2.1 and 8.4 Hz), 3.75 (s, 3H),3.71 (s, 3H); LCMS: purity: 87%, MS (m/e): 298 (M+). 418 2-Chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N4- LCMS: purity: 99%, MS (m/e): 354(M+). − − (methoxycarbonylmethyl)-4-pyrimidineamine 419 N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-[3- (oxazol-5-yl)phenyl]- 1 H NMR(DMSO-d6): d 9.29 (s, 1H), 9.21 (s, 1H), 8.33 (s, 1H), 8.07 + + −2,4-pyrimidinediamine (d, 1H, J = 3.0 Hz), 8.04 (s, 1H), 7.61 (bd, 1H),7.39 (s, 1H), 7.29 (bdd, 1H, J = 2.7 and 8.4 Hz), 7.25 (m, 3H), 6.76 (d,1H, J = 8.7 Hz), 3.70 (s, 3H), 3.64 (s, 3H); LCMS: purity: 98%, MS 420N4- (3,4-Ethylenedioxyphenyl)-5-fluoro-N2- (indol-6-yl)-N4- 1H NMR(DMSO-d6): d 10.77 (s, 1H), 9.05 (s, 1H), 7.94 (d, 1H, J = 5.7 + −(methoxycarbonylmethyl)-2,4-pyrimidinediamine Hz), 7.70 (s, 1H), 7.32(d, 1H, J = 2.8 Hz), 7.19 (d, 1H, J = 1.5 Hz), 7.17 (t, 1H, J = 3 Hz),6.82 (m, 3H), 6.28 (d, 1H, J = 2.1 Hz), 4.60 (s, 2H), 4.24 (s, 4H), 3.33(s, 3H); LCMS: purity: 99 421 N4- (3,4-Dimethoxyphenyl)-5-fluoro-N2-[2-(N- 1H NMR (DMSO-d6): d 11.66 (s, 1H), 9.27 (s, 1H), 9.22 (s, 1H),8.41 + − methylaminocarbonyl)indol-7-yl]-2,4-pyrimidinediamine (bd, 1H,J = 4.8 Hz), 8.09 (d, 1H, J = 3.3 Hz), 7.99 (d, 1H, J = 7.8 Hz), 7.33(dd, 1H, J = 2.4 and 8.4 Hz), 7.28 (d, 1H, J = 2.7 Hz), 7.18 (d, 1H, J =7.5 Hz), 7.03 (d, 1H, J = 2.1 Hz), 6.89 (m 422 N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-[4- (oxazol-5-yl)phenyl]- 1H NMR(DMSO-d6): d 9.36 (s, 1H), 9.24 (s, 1H), 8.33 (s, 1H), 8.07 + + −2,4-pyrimidinediamine (d, 1H, J = 3.9 Hz), 7.75 (d, 2H, J = 6.0 Hz),7.50 (d, 2H, J = 8.7 Hz), 7.75 (d, 2H, J = 8.7 Hz), 7.47 (s, 1H), 7.26(m, 2H), 6.92 (d, 1H, J = 9.6 Hz), 3.76 (s, 3H), 3.69 (s, 3H); LCMS:purity 423 N4- (3,4-Dimethoxyphenyl)-5-fluoro-N2-[3-(oxazol-2-yl)phenyl]- 1H NMR (DMSO-d6): d 9.36 (s, 1H), 9.22 (s, 1H),8.29 (s, 1H), 8.12 (s, + + − + 2,4-pyrimidinediamine 1H), 8.08 (d, 1H, J= 3 Hz), 7.81 (dd, 1H, J = 1.8 and 7.1 Hz), 7.49 (d, 1H, J = 6.9 Hz),7.31 (m, 4H), 6.79 (d, 1H, J = 8.7 Hz), 3.71 (s, 3H), 3.67 (s, 3H);LCMS: purity: 98%, MS (m/e): 40 424 N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-[4- (oxazol-2-yl)phenyl]- 1H NMR(DMSO-d6): d 9.50 (s, 1H), 9.28 (s, 1H), 8.09 (s and d, 2H, + −2,4-pyrimidinediamine J = 4.5 Hz), 7.76 (m, 4H), 7.28 (m, 3H), 6.93 (d,1H, J = 8.4 Hz), 3.76 (s, 3H), 3.70 (s, 3H); LCMS: purity: 89%, MS(m/e): 408 (M+). 425 N2- (3-Chloro-4-methoxyphenyl)-N4-(3,4-dimethoxyphenyl)-5- 1H NMR (DMSO-d6): d 9.17 (s, 1H), 9.08 (s, 1H),8.02 (d, 1H, J = 3.9 + + − fluoro-2,4-pyrimidinediamine Hz), 7.84 (s,1H, J = 2.7 Hz), 7.41 (dd, 1H, J = 3.0 and 9.3 Hz), 7.27 (dd, 1H, J =2.4 and 8.7 Hz), 7.21 (d, 1H, J = 2.4 Hz), 6.97 9d, 1H, J = 8.7 Hz),6.88 (d, 1H, J = 8.7 Hz), 3.77 (s, 3H), 426 N2-[3-(4-Acetylpiperazino)phenyl]-N4- (3,4- 1H NMR (DMSO-d6): d 9.13 (s, 1H),8.99 (s, 1H), 8.02 (d, 1H, J = 4.2 + + −ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine Hz), 7.22 (m, 4H),7.03 (m, 1H), 6.77 (d, 1H, J = 8.7 Hz), 6.50 (bd, 1H, J = 7.2 Hz), 4.21(bs, 4H), 3.02 (bm, 2H), 2.95 (bm, 2H), 2.02 (s, 3H); LCMS: purity: 97%,MS (m/e): 465 (MH+). 427 N2-[4- (4-Acetylpiperazino)phenyl]-N4- (3,4- 1HNMR (DMSO-d6): d 9.07 (s, 1H), 8.92 (s, 1H), 7.98 (d, 1H, J = 3.9 + + −ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine Hz), 7.48 (d, J =8.7 Hz), 7.33 (d, 1H, J = 2.4 Hz), 7.18 (dd, 1H, J = 2.1 and 8.7 Hz),6.83 (d, 1H, J = 9.3 Hz), 6.73 (d, 1H, J = 1H, J = 8.7 Hz), 4.23 (bs,4H), 3.56 (bs, 4H), 3.03 (t, 2H, J = 5 428 N2-[3-(4-Acetylpiperazino)phenyl]-N4- (3,5-dimethoxyphenyl)- 1H NMR (DMSO-d6):d 9.23 (s, 1H), 9.07 (s, 1H), 8.09 (d, 1H, J = 3 + −5-fluoro-2,4-pyrimidinediamine Hz), 7.26 (s, 1H), 7.15 (d, 1H, J = Hz),7.07 (t, 1H, J = 8.4 Hz), 6.97 (d, 2H, J = 2.4 Hz), 6.50 (bd, 1H, J =7.5 Hz), 6.18 (d, 1H, J = 2.1 Hz), 5.74 (s, 1H), 3.49 (m, 4H), 3.32 (s,6H), 2.96 ( 429 N2-[3- (4-Acetylpiperazino)phenyl]-N4-(3,4-dimethoxyphenyl)- 1H NMR (DMSO-d6): d 9.17 (bs, 1H), 8.99 (s, 1H),8.02 (d, 1H, J = 3.9 + − 5-fluoro-2,4-pyrimidinediamine Hz), 7.27 (m,2H), 7.01 (bd, 1H, J = 8.4 Hz), 7.00 (t, 1H, J = 8.1 Hz), 6.86 (d, 1H, J= 8.4 Hz), 6.48 (bd, 1H, J = 9.9 Hz), 6.13 (bs, 1H), 3.72 (s, 3H), 3.62(s, 3H), 3.46 (m, 4H), 2.96 (m, 430 N2-[4-(4-Acetylpiperazino)phenyl]-N4- (3,4-dimethoxyphenyl)- 1H NMR (DMSO-d6):d 9.11 (s, 1H), 8.88 (s, 1H), 7.98 (d, 1H, J = 3.9 + −5-fluoro-2,4-pyrimidinediamine Hz), 7.46 (d, 2H, J = 9.3 Hz), 7.27 (m,2H), 6.87 (d, 1H, J = 8.4 Hz), 6.80 (d, 2H, J = 9 Hz), 3.74 (s, 3H),3.65 (s, 3H), 3.56 (m, 4H), 3.02 (m, 2H), 2.96 (m, 2H), 2.03 (s, 3H);LCMS: purit 431 N2-[3- (4-Acetylpiperazino)phenyl]-5-fluoro-N4- (3,4- 1HNMR (DMSO-d6): d 9.62 (s, 1H), 9.19 (s, 1H), 8.14 (m, 1H), 7.62 + + −(tetrafluoroethylenedioxyphenyl)-2,4-pyrimidinediamine (dd, 1H, J = 2.7and 9.6 Hz), 7.39 (d, 1H, J = 9 Hz), 7.23 (d, 1H, J = 8 Hz), 7.16 (s,1H), 7.07 (t, 1H, J = 2.6 Hz), 6.55 (d, 1H, J = 2.6 Hz), 6.12 (s, 1H),3.54 (bs, 4H), 2.02 (s, 3H); LCMS: 432 N2-[4-(4-Acetylpiperazino)phenyl]-5-fluoro-N4- (3,4- 1H NMR (DMSO-d6): d 9.57(s, 1H), 9.11 (s, 1H), 8.15 (bd, 1H), 8.10 + −(tetrafluoroethylenedioxyphenyl)-2,4-pyrimidinediamine (d, 1H, J = 3.3Hz), 7.57 (bdd, 1H, J = 9.6 Hz), 7.45 (d, 2H, J = 8.7 Hz), 7.37 (d, 1H,J = 9 Hz), 6.87 (d, 2H, J = 9.3 Hz), 6.69 (d, 1H, J = 8.7 Hz), 6.47 (d,1H, J = 8.7 Hz), 3.52 (m, 4H), 2.99 433 N4- (3,4-Dimethoxyphenyl)-N2-(3,5-dimethylphenyl)-5-fluoro- 1H NMR (DMSO-d6): d 9.05 (s, 1H), 7.89(d, 1H, J = 6.0 Hz), 7.31 (s, + − N4-methyl-2,4-pyrimidinediamine 2H),6.93 (d, 1H, J = 2.7 Hz), 6.90 (s, 1H), 6.81 (dd, 1H, J = 2.4 and 8.1Hz), 6.50 (s, 1H), 3.75 (s, 3H), 3.71 (s, 1H), 3.42 (s, 3H), 2.18 (s,6H); LCMS: purity: 95%, MS (m/e): 383 (MH+). 434 N2-(3,5-Dimethoxyphenyl)-N4- (3,4-dimethoxyphenyl)-5-fluoro- LCMS: purity:96%, MS (m/e): 415 (MH+). + − N4-methyl-2,4-pyrimidinediamine 435 N4-(3,4-Dimethoxyphenyl)-N2-[2- (ethoxycarbonyl)indol-7-yl]-5- 1H NMR(DMSO-d6): d 11.94 (s, 1H), 9.32 (s, 1H), 8.15 (d, 1H, J = J = + −fluoro-N4-methyl-2,4-pyrimidinediamine 7.5 Hz), 7.97 (d, 1H, J = 6.0Hz), 7.22 (d, 1H, J = 7.8 Hz), 7.12 (d, 1H, J = 2.1 Hz), 6.96 (m, 3H),6.82 (m, 1H), 4.33 (q, 2H, J = 4.2 Hz), 3.76 (s, 3H), 3.72 (s, 3H), 3.46(s, 3H), 1.35 (t, 436 N4- (3,4-Dimethoxyphenyl)-5-fluoro-N2-(indol-6-yl)-N4-methyl- 1H NMR (DMSO-d6): d 10.85 (s, 1H), 9.07 (s, 1H),8.03 (s, 1H), 7.87 + − 2,4-pyrimidinediamine (d, 1H, J = 8.4 Hz), 7.34(d, 1H, J = 8.7 Hz), 7.16 (m, 2H), 6.93 (m, 2H), 6.90 (s, 1H), 6.80 (m,1H), 6.28 (s, 1H), 3.75 (s, 3H), 3.73 (s, 3H), 3.44 (s, 3H); LCMS:purity: 94%, MS (m/e): 3 437 N2-[4- (4-Acetylpiperazino)phenyl]-N4-(3,5-dimethoxyphenyl)- LCMS: purity: 80%, MS (m/e): 467 (MH+). + −5-fluoro-2,4-pyrimidinediamine 438 N4-(3,4-Dimethoxyphenyl)-5-fluoro-N4-methyl-N2-[3- (oxazol- 1 H NMR(DMSO-d6): d 9.42 (s, 1H), 8.40 (s, 1H), 8.28 (bs, 1H), 7.93 + + −5-yl)phenyl]-2,4-pyrimidinediamine (d, 1H, J = 8.7 Hz), 7.58 (bd, 1H, J= 6.8 Hz), 7.55 (s, 1H), 7.27 (m, 2H), 6.96 (d, 1H, J = 2.4 Hz), 6.92(m, 1H), 6.81 (dd, 1H, J = 2.1 and 8.4 Hz), 3.75 (s, 3H), 3.75 2 (s,3H), 3.47 (s, 439 N4- (3,4-Dimethoxyphenyl)-5-fluoro-N4-methyl-N2-[3-(oxazol- 1H NMR (DMSO-d6): d 9.50 (s, 1H), 8.62 (d, 1H, J = 3.6 Hz),8.17 (s, + + − − 2-yl)phenyl]-2,4-pyrimidinediamine 1H), 7.94 (d, 1H, J= 6.0 Hz), 7.70 (dd, 1H, J = 2.4 Hz), 7.33 (m, 2H), 6.97 (d, 1H, J = 2.4Hz), 6.92 (d, 1H, J = 8.4 Hz), 6.82 (dd, 1H, J = 2.4 and 8.7 Hz), 3.76(s, 3H), 3.73 (s, 3H), 3.48 440 N4-(3,4-Dimethoxyphenyl)-5-fluoro-N4-methyl-N2-[4- (oxazol- 1H NMR(DMSO-d6): d 9.59 (s, 1H), 8.10 (s, 1H), 7.98 (m, 2H), 7.62 + −2-yl)phenyl]-2,4-pyrimidinediamine (dd, 1H, J = 2.1 and 6.6 Hz), 7.27(s, 1H), 6.96 (m, 2H), 6.92 (s, 1H), 6.81 (dd, 2.4 and 8.4 Hz), 6.61(dd, 1H, J = 2.1 and 6.6 Hz), 5.67 (bs, 1H), 3.77 (s, 3H), 3.72 (s, 3H),3.45 (s, 3H). 441 N2- (3,5-Dimethylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5- LCMS: purity: 91%, MS 9m/e): 439 (MH+). + −fluoro-N4- (methoxycarbonylmethyl)-2,4-pyrimidinediamine 442 N2-(3,5-Dimethoxyphenyl)-N4- (3,4-ethylenedioxyphenyl)-5- 1H NMR (DMSO-d6):d 9.14 (s, 1H), 7.97 (d, 1H, J = 5.7 Hz), 6.84 (m, + − fluoro-N4-(methoxycarbonylmethyl)-2,4-pyrimidinediamine 5H), 6.07 (m, 1H), 4.62(s, 2H), 4.24 (s, 3H), 3.68 (bs, 4H), 3.34 (s, 6H); LCMS: purity: 94%,MS: 471 (MH+). 443 N4- (3,4-Ethylenedioxyphenyl)-5-fluoro-N4- 1H NMR(DMSO-d6): d 9.40 (s, 1H), 8.40 (s, 1H), 8.00 (d, 1H, J = J = + −(methoxycarbonylmethyl)-N2-[3- (oxazol-5-yl)phenyl]-2,4- 4.2 Hz), 7.93(bs, 1H), 7.60 (m, 1H), 7.57 (s, 1H), 7.27 (m, 2H), 6.83pyrimidinediamine (m, 3H), 4.63 (s, 2H), 4.23 (s, 4H), 3.51 (s, 3H);LCMS: purity: 95%, MS (m/e): 478 (MH+). 444 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4- 1H NMR (DMSO-d6): d 9.49 (s, 1H),8.24 (s, 1H), 8.17 (s, 1H), 8.00 + − (methoxycarbonylmethyl)-N2-[3-(oxazol-2-yl)phenyl]-2,4- (d, 1H, J = 5.7 Hz), 7.76 (bd, 1H, J = 9.6Hz), 7.51 (bd, 1H, J = 8.1 Hz), pyrimidinediamine 7.34 (m, 2H), 6.86 (m,1H), 6.83 (m, 1H), 4.64 (s, 2H), 4.24 (s, 4H), 3.54 (s, 3H); LCMS:purity: 91%, MS (m/e): 478 445 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4- 1H NMR (DMSO-d6): d 9.61 (s, 1H),8.10 (s, 1H), 8.05 (d, 1H, J = 8.1 + − (methoxycarbonylmethyl)-N2-[4-(oxazol-2-yl)phenyl]-2,4- Hz), 7.77 (dd, 2H, J = 8.4 Hz), 7.70 (dd, 2H,J = 8.4 Hz), 7.29 (s, 1H), pyrimidinediamine 6.85 (m, 3H), 4.64 (s, 2H),4.25 (s, 4H), 3.63 (s, 3H); LCMS: purity: 92%, MS (m/e): 478 (MH+). 446N4- (3,4-Ethylenedioxyphenyl)-5-fluoro-N4- 1H NMR (DMSO-d6): d 9.24 (s,1H), 7.97 (d, 1H, J = 5.7 Hz), 7.94 (m, + −(methoxycarbonylmethyl)-N2-[3- (N- 1H), 7.22 (m, 2H), 7.08 (t, 1H, J =7.8 Hz), 6.83 (m, 3H), 6.49 (m, 1H),methylamino)carbonylmethyleneoxyphenyl]-2,4- 4.62 (s, 2H), 4.39 (s, 2H),4.24 (s, 4H), 3.60 (s, 3H), 2.66 (d, 3H, J = pyrimidinediamine 5.1 Hz);LCMS: purity: 97%, MS (498 (MH+). 447 N4-(3,4-Dimethoxyphenyl)-5-fluoro-N4-methyl-N2-[3- (N- 1H NMR (DMSO-d6): d9.24 (s, 1H), 7.94 (bs, 1H), 7.90 (d, 1H, J = 5.7 + −methylamino)carbonylmethyleneoxyphenyl]-2,4- Hz), 7.46 (t, 1H, J = 2.1Hz), 7.27 (bd, 1H, J = 9 Hz), 7.10 (t, 1H, J = 5.1 pyrimidinediamineHz), 6.93 (m, 1H), 6.79 (dd, 1H, J = 2.7 and 8.7 Hz), 6.45 (dd, 1H, J =1.8 and 8.1 Hz), 6.12 (m, 1H), 4.38 (s, 2 448 N2-[4-Chloro-3-(N-methylamino)carbonylphenyl]-N4- (3,4- 1H NMR (DMSO-d6): d 9.37 (s,1H), 9.18 (s, 1H), 8.21 (d, 1H, J = 4.5 + + −ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine Hz), 8.05 (d, 1H, J= 3.6 Hz), 7.72 (m, 2H), 7.22 (m, 2H), 7.20 (m, 3H), 6.80 (bdd, 1H, J =2.1 and 9 Hz), 4.11 (bs, 4H), 2.71 (d, 3H, J = 4.5 Hz); LCMS: purity:95%; MS (m/e): 430 (MH+). 449 N2-[4-Chloro-3-(N-methylamino)carbonylphenyl]-N4- (3,4- 1H NMR (DMSO-d6): d 8.20 (d,1H), 8.05 (d, 1H, J = 3.9 Hz), 7.75 (d, + −dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 1H, J = 2.7 Hz), 7.66(dd, 1H, J = 3.0 and 8.7 Hz), 7.32 (dd, 1H, J = 2.4 and 9.0 Hz), 7.23(s, 1H), 7.18 (m, 1H), 6.88 (d, 1H, J = 8.7 Hz), 4.00 (s, 4H), 3.76 (s,3H), 3.71 (s, 3H), 2.69 (d, 450 N2-[4-Chloro-3-(N-methylamino)carbonylphenyl]-N4- (3,5- 1H NMR (DMSO-d6): d 8.15 (d,1H, J = 4.2 Hz), 7.82 (dd, 1H, J = 2.7 + −dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine and 9.0 Hz), 7.61 (d,1H, J = 2.7 Hz), 7.25 (d, 1H, J = 9.0 Hz), 6.96 (t, 2H, J = 2.4 Hz),6.26 (t, 1H, J = 2.1 Hz), 3.71 (s, 6H), 2.71 (d, 3H, 3.3 Hz); LCMS:purity: 87%, MS (m/e): 432 (M+). 451 N4-(3-Chloro-4-methoxyphenyl)-N2-[4-chloro-3- (N- 1H NMR (DMSO-d6): d 8.16(d, 1H, J = 3.9 Hz), 7.70 (d, 1H, J = 2.7 + +methylamino)carbonylphenyl]-5-fluoro-2,4-pyrimidinediamine Hz), 7.64 (m,2H), 7.30 (d, 1H, J = 9.3 Hz), 7.10 (d, 1H, J = 9 Hz), 3.87 (s, 3H),2.69 (s, 3H); LCMS: purity: 91%, MS (m/e): 536 (M+). 452 N4-[3-Chloro-4-(ethoxycarbonyl-1,1- 1H NMR (DMSO-d6): d 9.65 (bs, 2H), 8.26 (d, 1H, J =4.8 Hz), 8.17 (s, + + dimethylmethyleneoxy)phenyl]-N2-[4-chloro-3- (N-1H), 7.80-7.58 (m, 4H), 7.27 (d, 1H, J = 8.7 Hz), 6.89 (d, 1H, J = 9Hz), methylamino)carbonylphenyl]-5-fluoro-2,4-pyrimidinediamine 4.20 (q,2H, J = 6.9 Hz), 2.71 (d, 3H, J = 4.2 Hz), 1.54 (s, 6H), 1.21 (t, 3H, J= 7.2 Hz); LCMS: purity: 91%, MS (m/ 453 N2-[4-Chloro-3-(N-methylamino)carbonylphenyl]-N4- (3,4- 1H NMR (DMSO-d6): d 9.69 (s,1H), 8.28 (d, 1H, J = 4.5 Hz), 7.98 (d, + −ethylenedioxyphenyl)-5-fluoro-N4-methyl-4-pyrimidinediamine 1H, J = 6.0Hz), 7.83 (d, 1H, J = 2.4 Hz), 7.66 (dd, 1H, J = 2.7 and 8.7 Hz), 7.29(d, 1H, J = 9 Hz), 6.84 (m, 2H), 6.76 (dd, 1H, 2.7 and 8.7 Hz), 4.24 (s,4H), 3.38 (s, 1H), 2.72 (d, 3H, J= 454 N2-[4-Chloro-3-(N-methylamino)carbonylphenyl]-N4- (3,4- 1H NMR (DMSO-d6): d 9.50 (s,1H), 8.26 (d, 1H, J = 4.5 Hz), 7.93 (d, + −dimethoxyphenyl)-5-fluoro-N4-methyl-4-pyrimidinediamine 1H, 6.0 Hz),7.87 (d, 1H, J = 2.7 Hz), 7.68 (dd, 1H, J = 2.4 and 5.7 Hz), 7.26 (d,1H, J = 8.7 Hz), 6.93 (m, 2H), 6.80 (dd, 1H, J = 2.4 and 8.4 Hz), 3.76(s, 3H), 3.76 (s, 3H), 3.72 (s, 3H), 455 N2-[4-Chloro-3-(N-methylamino)carbonylphenyl]-N4- (2,2- 1H NMR (DMSO-d6): d 10.71 (s,1H), 9.87 (s, 1H), 8.26 (d, 1H, J = 4.2 + + −dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4- Hz), 8.16 (d, 1H,J = 4.2 Hz), 7.63 (m, 2H), 7.25 (m, 2H), 7.17 (d, 1H, pyrimidinediamineJ = 2.1 Hz), 6.90 (d, 1H, J = 8.7 Hz), 2.71 (d, 3H, J = 4.5 Hz), 1.40(s, 6H); LCMS: purity: 97%, MS (m/e): 471 (M+). 456 N2-[3-Chloro-4-(N-methylamino)carbonylphenyl]-N4- (2,2- 1H NMR (DMSO-d6): d 10.74 (s,1H), 10.34 (s, 1H), 10.09 (s, 1H), + + +dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4- 8.24 (d, 1H, J =4.8 Hz), 8.15 (d, 1H, J = 4.5 Hz), 7.83 (d, 1H, J = 1.5pyrimidinediamine Hz), 7.44 (dd, 1H, J = 1.8 and 8.4 Hz), 7.23 (m, 2H),6.93 (d, 1H, J = 8.4 Hz), 2.71 (d, 3H, J = 4.2 Hz), 1.40 (s, 6H); LCM457 N2- (2,6-Dimethoxypyrid-3-yl)-N4- (3,5-dimethoxyphenyl)-5- 1H NMR(DMSO-d6): d 8.02 (d, 1H, J = 8.4 Hz), 7.87 (d, 1H, J = 6.4 + + +fluoro-N4-methyl-2,4-pyrimidinediamine Hz), 7.76 (s, 1H), 6.41 (m, 3H),6.32 (d, 1H, J = J = 8.4 Hz), 3.89 (s, 3H), 3.82 (s, 3H), 3.71 (s, 3H),3.34 (s, 3H); LCMS: purity: 95%, MS (m/e): 416 (MH+). 458 N2-(2,6-Dimethoxypyrid-3-yl)-N4- (3,4-ethylenedioxyphenyl)-5- 1H NMR(DMSO-d6); d 8.02 (d, 1H, J = 8.4 Hz), 7.82 (d, 1H, J = 6.6 − −fluoro-N4-methyl-2,4-pyrimidinediamine Hz), 7.68 (s, 1H), 6.79 (m, 2H),6.72 (dd, 1H, J = 2.1 and 8.1 Hz), 6.30 (d, 1H, J = 8.1 Hz), 4.23 (s,4H), 3.89 (s, 3H), 3.81 (s, 3H), 3.28 (s, 3H); LCMS: purity: 97%, MS(m/e): 414 (MH+). 459 N4- (3,5-Dimethoxyphenyl)-N2-(2,6-dimethoxypyrid-3-yl)-5- 1 H NMR (DMSO-d6): d 9.12 (s, 1H), 7.97 (d,1H, J = 5.1 Hz), 7.89 (s, + − fluoro-2,4-pyrimidinediamine 1H), 7.82 (d,1H, J = 7.8 Hz), 6.95 (s, 1H), 6.28 (d, 1H, J = 7.8 Hz), 6.15 (s, 1H),3.84 (s, 3H), 3.83 (s, 3H), 23.64 (s, 6H); LCMS: purity: 85%, MS (m/e):402 (MH+). 460 N2- (2,6-Dimethoxypyrid-3-yl)-N4-(3,4-ethylenedioxyphenyl)-5- LCMS: purity: 93%, MS (m/e): 400 (MH+). + −fluoro-2,4-pyrimidinediamine 461 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-methyl-N4-methyl- 1H NMR(DMSO-d6): d 7.72 (d, 1H, J = 5.1 Hz), 6.79 (d, 1H, J = 9.0 − −2,4-pyrimidinediamine Hz), 6.73 (bs, 1H), 6.66 (bd, 1H), 2.74 (d, 3H, J= 4.5 Hz); LCMS: purity: 93%, MS (m/e): 291 (MH+). 462 N2-Dimethyl-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N4- 1H NMR (DMSO-d6): d 7.78 (d, 1H,J = 6.0 Hz), 6.80 (d, 1H, J = 8.4 − − methyl-2,4-pyrimidinediamine Hz),6.75 (d, 1H, J = 2.7 Hz), 6.66 (dd, 1H, J = 1.8 and 8.4 Hz), 4.22 (s,4H), 3.31 (s, 3H), 3.30 (s, 3H); LCMS: purity: 95%; MS (m/e): 305 (MH+).463 N2-[3-Chloro-4- (N-methylamino)carbonylphenyl]-N4- (3,4- 1H NMR(DMSO-d6): d 9.45 (s, 1H), 9.24 (s, 1H), 8.11 (m, 2H), 7.89 + + −ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine (d, 1H, J = 2.1 Hz),7.54 (dd, 2.1 and 8.7 Hz), 7.20 (m, 3H), 6.82 (d, 1H, J = 8.4 Hz), 4.22(bs, 4H), 2.71 (d, 3H, J = 4.5 Hz); LCMS: purity: 99%, MS (m/e): 430(MH+). 464 N2-[3-Chloro-4- (N-methylamino)carbonylphenyl]-N4- (3,4- 1HNMR (DMSO-d6): d 10.34 (s, 1H), 10.10 (s, 1H), 8.25 (d, 1H, J = + −dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 4.5 Hz), 8.18 (d, 1H, J= 4.8 Hz), 7.81 (s, 1H), 7.41 (d, 1H, J = 8.1 Hz), 7.27 (d, 1H, J = 8.4Hz), 7.18 (m, 2H), 6.95 (d, 1H, J = 8.7 Hz), 3.75 (s, 3H), 3.68 (s, 3H),2.71 (d, 3H); LCMS: puri 465 N2-[3-Chloro-4-(N-methylamino)carbonylphenyl]-N4- (3,5- LCMS: purity: 100%, MS (m/e):432 (MH+). + − dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 466 N4-(3-Chloro-4-methoxyphenyl)-N2-[3-chloro-4- (N- LCMS: purity: 100%, MS(m/e): 436 (MH+). + + −methylamino)carbonylphenyl]-5-fluoro-2,4-pyrimidinediamine 467N4-[3-Chloro-4- (ethoxycarbonyl-1,1- LCMS: purity: 95%, MS (m/e): 536(MH+). + + + dimethylmethyleneoxy)phenyl]-N2-[3-chloro-4- (N-methylamino)carbonylphenyl]-5-fluoro-2,4-pyrimidinediamine 468N2-[3-Chloro-4- (N-methylamino)carbonylphenyl]-5-fluoro-N4- LCMS:purity: 100%, MS (m/e): 388 (MH+). + + −(3-hydroxyphenyl)-2,4-pyrimidinediamine 469 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2- (2-hydroxyethyl)- 1H NMR(DMSO-d6): d 7.70 (d, 1H, J = 5.7 Hz), 6.79 (d, 1H, J = 8.7 − −N4-methyl-2,4-pyrimidinediamine Hz), 6.74 (d, 1H, J = 2.4 Hz), 6.66 (dd,1H, J = 2.4 and 8.4 Hz), 6.50 (t, 1H, J = 5.1 Hz), 4.61 (t, 1H, J = 5.4Hz), 4.22 (s, 4H), 3.47 (q, 2H, J = 6.3 Hz), 3.29 (t, 2H, J = 5.4 Hz),3.25 (s, 3H) 470 2-Chloro-N4-[3-chloro-4- (ethoxycarbonyl-1,1- 1H NMR(CDCl3): d 7.87 (d, 1H, J = 7.8 Hz), 7.25 (m, 1H), 6.95 (m, − +dimethylmethyleneoxy)phenyl]-5-fluoro-N4-methyl-4- 2H), 4.25 (q, 2H, J =4.8 Hz), 3.46 (s, 3H), 1.65 (s, 6H), 1.29 (t, 3H, J = pyrimidineamine4.8 Hz); LCMS: purity: 95%, MS (m/e): 404 (MH+; Cl37). 471 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-isopropyl-N4- 1H NMR (DMSO-d6): d7.70 (d, 1H, J = 5.7 Hz), 6.77 (d, 1H, J = 8.7 − −methyl-2,4-pyrimidinediamine Hz), 6.37 (d, 1H, J = 2.4 Hz), 6.68 (dd,1H, J = 2.4 and 8.7 Hz), 6.44 (d, 1H, J = 8.1 Hz), 4.22 (s, 4H), 3.90(sept, 1H, J = 7.5 Hz), 3.27 (s, 3H), 1.12 (d, 6H, J = 6.6 Hz); LCMS:purity: 93%, MS 472 N2- (2,6-Dimethoxypyrid-3-yl)-5-fluoro-N4-(3-hydroxyphenyl)- 1H NMR (DMSO-d6): d 10.39 (s, 1H), 9.52 (s, 1H), 8.20(d, 1H, J = 5.7 + − 2,4-pyrimidinediamine Hz), 7.77 (m, 1H), 7.08 (m,1H), 6.59 (m, 1H), 6.45 (d, 1H, J = 8.4 Hz), 6.37 (d, 1H, J = 8.1 Hz),3.88 (s, 3H), 3.86 (s, 3H); LCMS: purity: 89%, MS (m/e): 358 (MH+). 473N2-[3-Chloro-4- (N-methylamino)carbonylphenyl]-N4- (3,4- 1H NMR(DMSO-d6): d 9.71 (s, 1H), 8.16 (d, 1H, J = 4.5 Hz), 8.00 (d, + −ethylenedioxyphenyl)-5-fluoro-N4-methyl-2,4- 1H, J = 5.7 Hz), 7.95 (d,1H, J = 1.8 Hz) 7.53 (dd, 1H, J = 2.1 and 8.4 pyrimidinediamine Hz),7.29 (d, 1H, J = 8.4 Hz), 6.85 (m, 2H), 6.77 (dd, 1H, J = 2.1 and 8.4Hz), 4.24 (s, 4H), 3.40 (s, 3H), 2.71 (d, 3H, 474 N2-[3-Chloro-4-(N-methylamino)carbonylphenyl]-N4- (3,4- 1H NMR (DMSO-d6): d 9.86 (bs,1H), 8.18 (d, 1H, J = 4.5 Hz), 8.03 + −dimethoxyphenyl)-5-fluoro-N4-methyl-2,4-pyrimidinediamine (dd, 1H, J =1.2 and 6.3 Hz), 7.94 (d, 1H, J = 1.8 Hz), 7.52 (dd, 1H, J = 2.1 and 8.4Hz), 7.30 (d, 1H, J = 8.4 Hz), 6.99 (d, 1H, J = 2.4 Hz), 6.93 (d, 1H, J= 8.4 Hz), 6.86 (dd, 1H, J = 2.4 and 8. 475 N4-[4-Chloro-3-(N-methylamino)carbonylphenyl]-N2- (3,5- 1H NMR (DMSO-d6): d 10.11 (s,1H), 9.83 (s, 1H), 8.30 (d, 1H, J = 4.5 + + −dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine Hz), 8.24 (d, 1H, J =4.5 Hz), 8.00 (dd, 1H, J = 2.7 and 8.7 Hz), 7.63 (d, 1H, J = 2.4 Hz),7.36 (d, 1H, J = 8.7 Hz), 6.78 (d, 2H, J = 2.1 Hz), 6.20 (t, 1H, J = 2.1Hz), 3.67 (s, 6H), 2.73 (d, 476 N4-[4-Chloro-3-(N-methylamino)carbonylphenyl]-N2- (3,5- 1H NMR (DMSO-d6): d 9.91 (s,1H), 9.52 (s, 1H), 8.29 (d, 1H, J = 4.8 + + −dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine Hz), 8.19 (d, 1H, J = 4.2Hz), 8.00 (bdd, 1H, J = 8.7 Hz), 7.62 (d, 1H, J = 2.1 Hz), 7.38 (d, 1H,J = 9.0 Hz), 7.17 (s, 2H), 6.63 (s, 1H), 2.72 (d, 3H, J = 4.8 Hz), 2.19(s, 6H); LCMS: purity: 477 N4-[4-Chloro-3-(N-methylamino)carbonylphenyl]-5-fluoro-N2- 1H NMR (DMSO-d6): d 9.55 (s,1H), 9.32 (s, 1H), 8.31 (bd, 1H), 8.15 + + − [3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- (bs, 1H), 7.99 (m, 2H),7.79 (m, 1H), 7.39 (d, 1H, J = 9 Hz), 7.29 (m, pyrimidinediamine 2H),7.14 (m, 1H), 6.49 (bd, 1H, J = 7.8 Hz), 4.36 (s, 2H), 2.72 (s, 3H),2.64 (s, 3H); LCMS: purity: 99%, MS (m/e): 4 478 N2-[3-Chloro-4-(N-methylamino)carbonylphenyl]-N4-[4-chloro- 1H NMR (DMSO-d6): d 9.69(s, 1H), 8.34 (d, 1H, J = 4.5 Hz), 8.22 (d, + − 3-(N-methylamino)carbonylphenyl]-5-fluoro-2,4- 1H, J = 3.6 Hz), 8.17 (d,1H, J = 4.5 Hz), 7.95 (dd, 1H, J = 2.7 and 8.7 pyrimidinediamine Hz),7.81 (d, 1H, J = 2.1 Hz), 7.71 (d, 1H, J = 2.7 Hz), 7.56 (dd, 1H, J =2.1 and 8.4 Hz), 7.43 (d, 1H, J = 9.0 Hz), 7.3 479 N4-[4-Chloro-3-(N-methylamino)carbonylphenyl]-N2- (indol-6- 1H NMR (DMSO-d6): d 11.98(s, 1H), 10.28 (s, 1H), 10.05 (s, 1H), + − yl)-2,4-pyrimidinediamine8.35 (d, 1H, J = 4.2 Hz), 8.21 (d, 1H, J = 4.8 Hz), 7.86 (bd, 1H, J =8.7 Hz), 7.77 (d, 1H, J = 2.7 Hz), 7.54 (s, 1H), 7.47 (d, 1H, J = 8.4Hz), 7.35 (d, 1H, J = 8.7 Hz), 7.30 (m, 1H), 7.05 (dd, 1 480 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-2-methoxy-N4-methyl- LCMS: purity:97%, MS (m/e): 292 (M+). − − 4-pyrimidineamine 481 N4-[3-Chloro-4-(N-methylamino)carbonylphenyl]-N2- (3,5- 1H NMR (DMSO-d6): d 9.85 (bs,1H), 9.50 (bs, 1H), 8.22 (m, 2H), + + −dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.89 (m, 2H), 7.33 (d,1H, J = 9.0 Hz), 6.85 (d, 2H, J = 1.5 Hz), 6.13 (d, 1H, J = 1.8 Hz),3.66 (s, 1H), 2.74 (d, 3H, J = 4.5 Hz); LCMS: purity: 98%, MS (m/e): 432(M+). 482 N4-[3-Chloro-4- (N-methylamino)carbonylphenyl]-N2- (3,5- 1HNMR (DMSO-d6): d 10.01 (s, 1H), 9.65 (s, 1H), 8.24 (d, 1H, J = 4.5 + + −dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine Hz), 7.85 (bs, 1H), 7.35(d, 1H, J = 8.7 Hz), 7.16 (s, 2H), 6.94 (s, 2H), 6.65 (s, 1H), 2.74 (d,3H, J = 4.8 Hz), 2.29 (s, 3H), 2.20 (s, 3H); LCMS: purity: 98%, MS(m/e): 400 (M+). 483 N4-[3-Chloro-4-(N-methylamino)carbonylphenyl]-5-fluoro-N2- 1H NMR (DMSO-d6): d 9.82(bs, 1H), 9.56 (bs, 1H), 8.22 (m, 2H), + [3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- 7.98 (bd, 1H), 7.91 (d,1H, J = 1.5 Hz), 7.82 (bd, 1H, J = 8.7 Hz), 7.37 pyrimidinediamine (d,1H, J = 8.7 Hz), 7.22 (m, 3H), 6.56 (m, 1H), 4.38 (s, 2H), 2.74 (d, 3H,J = 4.5 Hz), 2.64 (d, 3H, J = 4.8 Hz); LCMS: pu 484 N2-[4-Chloro-3-(N-methylamino)carbonylphenyl]-N4-[3-chloro- 1H NMR (DMSO-d6): d 9.69(s, 1H), 9.60 (s, 1H), 8.25 (m, 3H), 7.85 − 4-(N-methylamino)carbonylphenyl]-5-fluoro-2,4- (m, 3H), 7.36 (m, 3H), 2.75(d, 3H, J 4.8 Hz), 2.70 (d, 3H, J = 4.5 Hz); pyrimidinediamine LCMS:purity: 86%, MS (m/e): 463 (M+). 485 N4-[3-Chloro-4-(N-methylamino)carbonylphenyl]-5-fluoro-N2- 1H NMR (DMSO-d6): d 10.99(s, 1H), 10.10 (s, 1H), 9.80 (bs, 1H), + +(indol-6-yl)-2,4-pyrimidinediamine 8.25 (d, 1H, J = 4.5 Hz), 8.20 (d,1H, J = 4.2 Hz), 7.93 (d, 1H, J = 1.8 Hz), 7.83 (bd, 1H, J = 9.6 Hz),7.58 (s, 1H), 7.47 (m, 2H), 7.30 (m, 2H), 7.12 (bd, 1H, J = 8.1 Hz),6.38 (s, 1H); LCMS: p 486 N4-(2-Aminopyrid-6-yl)-2-chloro-5-fluoro-4-pyrimidineamine 1H NMR (CD3OD):d 8.16 (d, 1H, J = 3.6 Hz), 7.46 (m, 2H), 6.32 (dd, − − 1H, J = 3.9 and5.1 Hz); LCMS: purity: 92%, MS (m/e): 240 (M+). 487 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-methyl-2,4- 1H NMR (CD3OD): d 7.43(d, 1H, J = 7.2 Hz), 6.83 (d, 1H, J = 8.4 Hz), − − pyrimidinediamine6.78 (d, 1H, J = 2.4 Hz), 6.72 (dd, 1H, J = 2.7 and 8.4 Hz), 4.25 (s,4H), 3.40 (s, 3H); LCMS: purity: 100%, MS (m/e): 278 (MH+). 4882-Chloro-N4- (3,5-dimethoxyphenyl)-5-fluoro-N4-methyl-4- 1H NMR (CD3OD):d 7.93 (d, 1H, J = 5.4 Hz), 6.46 (s, 3H,), 4.62 (s, + − pyrimidineamine6H), 3.77 (s, 3H); LCMS: purity: 100%, MS (m/e): 298 (MH+). 489 N2-(2-Ethoxycarbonylindol-7-yl)-5-fluoro-N4- (2-hydroxyethyl)- 1H NMR(CD3OD): d 7.73 (m, 2H), 7.34 (dd, 1H, J = 1.2 and 8.1 Hz), − −2,4-pyrimidinediamine 7.17 (s, 1H), 7.04 (t, 2H, J = 7.8 Hz), 4.38 (q,2H, J = 6.9 Hz), 3.69 (t, 2H, J = 5.1 Hz), 3.58 (t, 2H, J = 6.6 Hz),1.42 (t, 3H, J = 7.2 Hz); LCMS: purity: 98%, MS (m/e): 360 (MH+). 4902-Chloro-N4- (2,6-dimethoxypyrid-5-yl)-5-fluoro-N4-methyl-4- 1H NMR(CD3OD): d 7.89 (d, 1H, J = 5.7 Hz), 7.57 (d, 1H, J = 8.1 Hz), − −pyrimidineamine 6.37 (d, 1H, J = 8.7 Hz), 3.94 (s, 3H), 3.91 (s, 3H),3.37 (s, 3H); LCMS: purity: 97%, MS (m/e): 299 (MH+). 491 2-Chloro-N4-(3,5-dichloro-4-methoxyphenyl-5-fluoro-N4- 1H NMR (CD3OD): d 8.02 (d,1H, J = 5.4 Hz), 7.43 (s, 2H), 3.91 (s, − − methyl-4-pyrimidineamine3H), 3.47 (s, 3H); LCMS: purity: 89%, MS (m/e): 366 (MH+). 492 N2-(Bis-2-hydroxyethyl)-N4- (3,4-ethylenedioxyphenyl)-5- 1H NMR (DMSO-d6):d 7.76 (d, 1H, J = 4.7 Hz), 6.79 (d, 1H, J = 6.3 − −fluoro-N4-methyl-2,4-pyrimidinediamine Hz), 6.75 (d, 1H, J = 2.4 Hz),6.67 (dd, 1H, J = 2.7 and 9.3 Hz), 4.71 (bs, 2H), 4.22 (bs, 4H), 3.57(bs, 4H), 3.31 (bs, 4H), 3.28 (s, 3H); LCMS: purity: 97%, MS (m/e): 416(MH+). 493 N4- (3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4- (N- 1H NMR(DMSO-d6): d 9.58 (s, 1H), 9.29 (s, 1H), 8.11 (d, 1H, J = 3.6 + + −methylamino)sulfonyl-3-methoxyphenyl]-2,4-pyrimidinediamine Hz), 7.47(m, 2H), 7.42 (bdd, 1H), 7.27 (d, 1H, J = 2.1 Hz), 7.13 (dd, 1H, J = 2.1and 8.4 Hz), 6.79 (d, 1H, J = 8.7 Hz), 6.73 (m, 1H), 4.22 (s, 4H), 3.68(s, 3H), 2.34 (d, 3H, J = 4.8 Hz); L 494 N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-[3-methoxyphenyl-4- 1H NMR (DMSO-d6):d 9.57 (s, 1H), 9.33 (s, 1H), 8.11 (d, 1H, J = 3.6 + + −(N-methylamino)sulfonyl]-2,4-pyrimidinediamine Hz), 7.51 (d, 1H, J = 1.8Hz), 7.45 (d, 1H, J = 8.4 Hz), 7.34 (dd, 1H, J = 1.8 and 8.7 Hz), 7.24(m, 2H), 6.90 (d, 1H, J = 9.0 Hz), 6.72 (d, 1H, J = 4.8 Hz), 3.75 (s,3H), 3.67 (s, 3H), 3.63 ( 495 N4-(3,5-Dimethoxyphenyl)-5-fluoro-N2-[3-methoxyphenyl-4- 1H NMR (DMSO-d6):d 9.64 (s, 1H), 9.37 (s, 1H), 8.16 (bd, 1H), 7.51 + −(methylamino)sulfonyl]-2,4-pyrimidinediamine (m, 3H), 6.97 (bs, 2H),6.71 (bd, 1H), 6.24 (bs, 1H), 3.69 (s, 6H), 3.31 (s, 3H), 2.34 (d, 3H, J= 4.8 Hz); LCMS: purity: 94%, MS (m/e): 464 (M+). 496 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 10.62 (s, 1H), 9.50 (s, 1H), 9.43 (s, 1H), 8.12 + + +[3-methoxyphenyl-4- (methylamino)sulfonyl]-2,4- (d, 1H, J = 3.9 Hz),7.46 (s, 1H), 7.44 (s, 1H), 7.26 (dd, 1H, J = 2.4 and pyrimidinediamine8.7 Hz), 7.14 (d, 1H, J = 2.4 Hz), 6.90 (d, 1H, J = 8.4 Hz), 6.70 (d,1H, J = 5.4 Hz), 3.69 (s, 3H), 2.32 (d, 3H, J = 497 N4-(4-Chloro-3-trifluoromethylphenyl)-5-fluoro-N2-[3- 1H NMR (DMSO-d6): d9.88 (s, 1H), 9.72 (s, 1H), 8.26 (m, 2H), 8.18 + + − methoxyphenyl-4-(methylamino)sulfonyl]-2,4- (d, 1H, J = 4.5 Hz), 7.65 (d, 1H, J = 8.7Hz), 7.51 (d, 1H, J = 8.7 Hz), pyrimidinediamine 7.44 (m, 2H), 6.74 (d,1H, J = 8.4 Hz), 3.72 (s, 3H), 2.34 (d, 3H, J = 5.1 Hz); LCMS: purity:97%, MS (m/e): 506 (M+). 498 N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[4- (3- 1H NMR(DMSO-d6): d 9.78 (s, 1H), 9.72 (s, 1H), 8.25 (m, 1H), 8.15 + + −methoxyphenyl-N-methylamino)sulfonyl]-2,4- (d, 1H, J = 3.6 Hz), 7.84(dd, 1H, J = 2.4 and 9.0 Hz), 7.52 (m, 2H), 7.43 pyrimidinediamine (m,2H), 6.74 (m, 1H), 3.74 (s, 3H), 2.33 (d, 3H, J = 2.1 Hz); LCMS: purity:83%, MS (m/e): 522 (M+). 499 5-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-methoxyphenyl-4- (N- 1H NMR (DMSO-d6): d 9.57(s, 1H), 9.38 (s, 1H), 9.31 (s, 1H), 8.13 + + −methylamino)sulfonyl]-2,4-pyrimidinediamine (d, 1H, J = 3.9 Hz), 7.51(m, 1H), 7.47 (m, 2H), 7.21 (d, 1H, J = 1.5 Hz), 7.08 (m, 2H), 6.70 (d,1H, J = 5.4 Hz), 6.51 (bdd, 1H, J = 8.1 Hz), 3.31 (s, 3H), 2.30 (d, 3H,J = 2.4 Hz); LCMS: puri 500 N4-(2,6-Dimethoxypyrid-3-yl)-N2,N4-dimethyl-5-fluoro-2,4- 1H NMR (DMSO-d6):d 7.66 (d, 1H, J = 5.4 Hz), 7.59 (d, 1H, J = 7.5 − − pyrimidinediamineHz), 6.54 (bd, 1H), 6.35 (d, 1H, J = 8.4 Hz), 3.85 (s, 3H), 3.83 (s,3H), 2.71 (d, 3H, J = 3.9 Hz); LCMS: purity: 92%, MS (m/e): 294 (M+).501 N4- (3,5-Dichloro-4-methoxyphenyl)-N2,N4-dimethyl-5-fluoro- 1H NMR(DMSO-d6): d 7.86 (d, 1H, J = 5.4 Hz), 7.42 (s, 2H), 3.80 (s, − −2,4-pyrimidinediamine 3H), 3.38 (s, 3H), 2.73 (d, 3H, J = 4.8 Hz); LCMS:purity: 98%, MS (m/e): 331 (M+). 502 2-Chloro-5-fluoro-N4-[4-(N-methylamino)sulfonyl-3- 1H NMR (DMSO-d6): d 10.28 (s, 1H), 8.42 (d,1H, J = 3.0 Hz), 7.71 (d, − − methoxyphenyl]-2,4-pyrimidineamine 1H, J =1.8 Hz), 7.67 (d, 1H, J = 8.4 Hz), 7.46 (dd, 1H, J = 1.5 and 8.4 Hz),6.95 (d, 1H, J = 5.4 Hz), 3.87 (s, 3H), 2.38 (2.38 (d, 3H, J = 4.8 Hz);LCMS: purity: 80%, MS (m/e): 349 (M + 2). 503 N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-[2- (2- 1H NMR (DMSO-d6): d 9.34 (s,1H), 9.14 (s, 1H), 8.57 (d, 1H, J = 2.7 + + −hydroxyethyleneoxy)pyrid-5-yl]-2,4-pyrimidinediamine Hz), 8.08 (d, 1H, J= 3.0 Hz), 7.98 (dd, 1H, J = 2.7 and 8.7 Hz), 6.91 (d, 2H, J = 1.8 Hz),6.77 (d, 1H, J = 8.7 Hz), 6.03 (t, 1H, J = 3.6 Hz), 4.23 (t, 2H, J = 4.5Hz), 3.69 (m, 2H), 3.65 (s, 504 N2- (3,5-Dimethylphenyl)-5-fluoro-N4-[2-(2- 1H NMR (DMSO-d6): d 9.30 (s, 1H), 9.06 (s, 1H), 8.54 (d, 1H, J =2.4 + + − hydroxyethyleneoxy)pyrid-5-yl]-2,4-pyrimidinediamine Hz), 8.06(d, 1H, J = 3.6 Hz), 7.94 (dd, 1H, J = 2.7 and 9.0 Hz), 7.20 (d, 2H, J =0.9 Hz), 6.79 (d, 1H, J = 9.0 Hz), 6.50 (s, 1H), 4.8 (t, 1H, J = 5.7Hz), 4.23 (t, 2H, J = 5.7 Hz), 3.70 (q, 2 505 N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4-[2- (2- 1H NMR (DMSO-d6): d 9.35(s, 1H), 9.17 (s, 1H), 8.49 (s, 1H), 8.07 + + −hydroxyethyleneoxy)pyrid-5-yl]-2,4-pyrimidinediamine (d, 1H, J = 3.6Hz), 7.98 (dd, 1H, J = 2.7 and 9.0 Hz), 7.81 (s, 1H), 7.40 (bd, 1H, J =8.7 Hz), 6.98 (d, 1H, J = 8.4 Hz), 6.80 (d, 1H, J = 8.7 Hz), 4.83 (t,1H, J = 5.7 Hz), 4.24 (t, 1H, J = 4.8 506 N2-Allyl-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-methyl-2,4- 1H NMR (DMSO-d6): d7.70 (d, 1H, J = 4.4 Hz), 7.68 (m, 2H), 7.66 (dd, − − pyrimidinediamine1H, J = 1.2 and 7.8 Hz), 5.85 (m, 1H), 5.10 (dd, 1H, J = 1.5 and 16.8Hz), 5.00 (dd, 1H, J = 1.8 and 12.0 Hz), 4.22 (s, 4H), 3.83 (t, 2H, J =4.5 Hz), 3.28 (s, 3H); LCMS: purity: 100%, MS (m 507 N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4-[4- (N- LCMS: purity: 80%, MS (m/e):464 (MH+). + + −methylamino)sulfonyl-3-methoxyphenyl]-2,4-pyrimidinediamine 508 N2-(3,5-Dimethoxyphenyl)-5-fluoro-N4- (3-methylpyrid-6-yl)- 1H NMR(DMSO-d6): d 9.50 (s, 1H), 9.22 (s, 1H), 8.16 (s, 1H), 8.13 + + −2,4-pyrimidinediamine (dd, 1H, J = 0.9 and 6.6 Hz), 8.06 (d, 1H, J = 8.7Hz), 7.55 (bdd, 1H, J = 5.7 Hz), 6.94 (d, 2H, J = 1.2 Hz), 6.07 (t, 1H,J = 1.2 Hz), 3.68 (s, 3H), 3.66 (s, 3H), 2.49 (s, 6H); LCMS: purity: 9509 N2- (3,5-Dimethylphenyl)-5-fluoro-N4- (3-methylpyrid-6-yl)-2,4- 1HNMR (DMSO-d6): d 9.46 (s, 1H), 9.14 (s, 1H), 3.17 (bs, 1H), 8.13 + + −pyrimidinediamine (d, 1H, J = 3.3 Hz), 8.04 (d, 1H, J = 8.4 Hz), 7.55(dd, 1H, J = 2.1 and 8.4 Hz), 7.24 (s, 2H), 6.24 (s, 1H), 3.33 (s, 3H),3.32 (s, 3H), 2.18 (s, 3H);; LCMS: purity: 93%, MS (m/e): 324 (MH+ 510N4- (5-Chloropyrid-2-yl)-N2- (3,5-dimethoxyphenyl)-5-fluoro- LCMS:purity: 93%, MS (m/e): 376 (MH+). + + − 2,4-pyrimidinediamine 5115-Fluoro-N4- (3-hydroxyphenyl)-N2-[3- (oxazol-2-yl)phenyl]-2,4- 1H NMR(DMSO-d6): d 9.39 (s, 1H), 9.30 (s, 1H), 9.22 (s, 1H), 8.29 +pyrimidinediamine (bs, 1H), 8.14 (s, 1H), 8.11 (d, 1H, J = 3.9 Hz), 7.90(dd, 1H, J = 1.2 and 9.0 Hz), 7.50 (dd, 1H, J = 1.5 and 6.3 Hz), 7.33(m, 3H), 7.09 (t, 1H, J = 2.1 Hz), 7.01 (t, 1H, J = 8.1 Hz), 6.45 9d 512N4- (3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3- (1,2,4-oxadiazol- 1H NMR(DMSO-d6): d 9.54 (s, 1H), 9.26 (s, 1H), 8.18 (s, 1H), 8.10 + −3-yl)phenyl]-2,4-pyrimidinediamine (d, 1H, J = 2.4 Hz), 7.83 (bd, 1H, J= 8.1 Hz), 7.38 (t, 1H, J = 7.8 Hz), 7.27 (m, 2H), 7.13 (bd, 1H, J = 8.7Hz), 6.82 (d, 1H, j = 9.0 Hz), 4.22 (s, 4H); LCMS: purity: 91%, MS(m/e): 406 (M+). 513 N4- (3,4-Dimethoxyphenyl)-5-fluoro-N2-[3-(1,2,4-oxadiazol-3- 1H NMR (DMSO-d6): d 9.53 (s, 1H), 9.29 (s, 1H), 8.21(s, 1H), 8.10 + − yl)phenyl]-2,4-pyrimidinediamine (d, 1H, J = 3.9 Hz),7.79 (dd, 1H, J = 1.2 and 8.4 Hz), 7.33 (m, 3H), 7.16 (s, 1H), 6.94 (d,1H, J = 8.7 Hz), 3.75 (s, 3H), 3.70 (s, 3H); LCMS: purity: 95%, MS(m/e): 407 (MH−). 514 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 1.6 (s, 1H), 9.49 (s, 1H), 9.40 (, s, 1H), 8.15 + − [3-(1,2,4-oxadiazol-3-yl)phenyl]-2,4-pyrimidinediamine (d, 1H, J = 8.1 Hz),8.11 (d, 1H, J = 3.9 Hz), 7.85 (bd, 1H, J = 8.4 Hz), 7.29 (m, 3H), 7.13(d, 1H, J = 2.4 Hz), 6.91 (dd, 1H, J = 3.0 and 8.4 Hz), 5.73 (d, 1H, J =3.6 Hz), 1.40 (s, 3H); LCMS 515 N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-[5-methoxycarbonyl-3- 1H NMR(DMSO-d6): d 9.61 (s, 1H), 9.27 (s, 1H), 8.62 (s, 1H), 8.38 (s, + −(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 1H), 8.17 (d, 1H, J = 0.9Hz), 8.12 (d, 1H, J = 3.6 Hz), 8.04 (d, 1H, J = 1.5 Hz), 7.35 (m, 2H),7.27 (m, 1H), 6.76 (d, 1H, J = 7.8 Hz), 3.82 (s, 3H), 3.70 (s, 3H), 3.65(s, 3H); LCMS: pur 516 N4- (3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[5- 1HNMR (DMSO-d6): d 9.64 (s, 1H), 9.23 (s, 1H), 8.61 (s, 1H), 8.37 (s, − −methoxycarbonyl-3- (oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 1H), 8.19(s, 1H), 8.12 (d, 1H, J = 3.3 Hz), 8.05 (s, 1H), 7.38 (m, 2H), 7.22 (dd,1H, J = 2.7 and 8.7 Hz), 6.70 (d, 1H, J = 8.7 Hz), 5.74 (s, 1H), 4.15(s, 4H), 3.85 (s, 3H); LCMS: purit 517 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 10.51 (s, 1H), 9.54 (s, 1H), 9.40 (s, 1H), 8.63 − −[5-methoxycarbonyl-3- (oxazol-2-yl)phenyl]-2,4- (s, 1H), 8.39 (s, 1H),8.18 (s, 1H), 8.14 (d, 1H, J = 3.9 Hz), 8.04 (s, 1H), pyrimidinediamine7.44 (dd, 1H, J = 2.1 and 8.7 Hz), 7.37 (s, 1H), 6.77 (d, 1H, J = 8.4Hz), 3.84 (s, 3H), 1.38 (s, 6H); LCMS: puri 518 5-Fluoro-N4-(3-hydroxyphenyl)-N2-[5-methoxycarbonyl-3- 1H NMR (DMSO-d6): d 9.64 (s,1H), 9.25 (s, 1H), 8.62 (s, 1H), 8.43 (s, + −(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 1H), 8.19 (s, 1H), 8.15 (d,1H, J = 3.9 Hz), 8.05 (s, 1H), 7.38 (s, 2H), 7.36 (s, 2H), 7.13 (s, 1H),6.98 (t, 1H, J = 8.7 Hz), 6.42 (dd, 1H, J = 2.4 and 6.6 Hz), 3.83 (s,3H); LCMS: purit 519 N4- (3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(oxazol-2-yl)-5- 1H NMR (DMSO-d6): d 9.75 (s, 1H), 9.23 (s, 1H), 8.59(s, 1H), 8.22 (t, + − trifluoromethylphenyl]-2,4-pyrimidinediamine 2H, J= 0.9 Hz), 8.14 (d, 1H, J = 3.9 Hz), 7.69 (s, 1H), 7.40 (s, 1H), 7.31(d, 1H, J = 2.4 Hz), 7.19 (dd, 1H, J = 2.7 and 9.0 Hz), 6.72 (d, 1H, J =8.4 Hz), 4.17 (s, 4H); LCMS: purity: 92% 520 N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-[3- (oxazol-2-yl)-5- 1H NMR (DMSO-d6):d 9.73 (s, 1H), 9.31 (s, 1H), 8.57 (s, 1H), 8.24 (s, + −trifluoromethylphenyl]-2,4-pyrimidinediamine 1H), 8.20 (bs, 1H), 8.14(d, 1H, J = 4.2 Hz), 7.68 (s, 1H), 7.40 (s, 1H), 7.33 (bdd, 1H, J = 9.0Hz), 7.23 (bs, 1H), 6.82 (d, 1H, J = 7.5 Hz), 3.71 (s, 3H), 3.68 (s,3H); LCMS: purity: 97 521 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 10.54 (s, 1H), 9.70 (s, 1H), 9.42 (s, 1H), 8.54 + − [3-(oxazol-2-yl)-5-trifluoromethylphenyl]-2,4-pyrimidinediamine (s, 1H),8.27 (s, 1H), 8.21 (s, 1H), 8.16 (d, 1H, J = 2.7 Hz), 7.67 (s, 1H), 7.40(d, 1H), 7.33 (bdd, 1H, J = 8.4 Hz), 7.17 (d, 1H, J = 2.4 Hz), 6.81 (d,1H, J = 8.4 Hz), 1.39 (s, 6H); LCMS: 522 5-Fluoro-N4-(3-hydroxyphenyl)-N2-[3- (1,2,4-oxadiazol-3- 1H NMR (DMSO-d6): d 9.55(s, 1H), 9.36 (s, 1H), 9.30 (s, 1H), 8.13 +yl)phenyl]-2,4-pyrimidinediamine (m, 2H), 7.88 (bd, 1H, J = 7.8 Hz),7.38 (t, 1H, J = 7.8 Hz), 7.27 (m, 2H), 7.13 (t, 1H, J = 7.8 Hz), 7.02(s, 1H), 6.50 (bdd, 1H, J = 5.7 Hz); LCMS: purity: 95%; MS (m/e): 364(M+). 523 2-Chloro-5-fluoro-N4-methyl-N4- (3,4,5-trimethoxyphenyl)-4- 1HNMR (DMSO-d6): d 8.11 (d, 1H, J = 5.4 Hz), 6.79 (s, 2H), 3.74 (s, −pyrimidineamine 3H), 3.72 (s, 3H), 3.65 (s, 3H), 3.38 (s, 3H); LCMS:purity: 94%, MS (m/e): 329 (MH+). 524 5-Fluoro-N4-(5-methylisoxazol-3-yl)-N2-[3- (oxazol-2- 1H NMR (DMSO-d6): d 10.45 (s,1H), 9.59 (s, 1H), 8.33 (s, 1H), 8.21 + yl)phenyl]-2,4-pyrimidinediamine(d, 1H, J = 2.7 Hz), 8.18 (s, 1H), 7.83 (bd, 1H, J = 7.2 Hz), 7.55 (bd,1H, J = 8.1 Hz), 7.40 (t, 1H, J = 8.1 Hz), 7.35 (s, 1H, J = 6.92 (s,1H), 2.29 9s, 3H); LCMS: purity: 100%, MS (m/e): 35 525 5-Fluoro-N4-(5-methyl-3-phenylisoxazol-4-yl)-N2-[3- (oxazol-2- 1H NMR (DMSO-d6): d9.33 (s, 1H), 9.06 (s, 1H), 8.23 (s, 1H), 8.14 +yl)phenyl]-2,4-pyrimidinediamine (bs, 1H), 8.09 (d, 1H, J = 3.6 Hz),7.66 (m, 3H), 7.43 (m, 4H), 7.32 (s, 1H), 7.24 (t, 1H, J = 7.2 Hz), 2.36(s, 3H); LCMS: purity: 85%, MS (m/e): 429 (MH+). 526 5-Fluoro-N4-(1-methyl-3-phenylpyrazol-5-yl)-N2-[3- (oxazol-2- 1H NMR (DMSO-d6): d9.48 (m, 2H), 8.19 (m, 2H), 8.11 (m, 2H), 7.77 +yl)phenyl]-2,4-pyrimidinediamine (m, 2H), 7.35 (m, 6H), 6.73 (s, 1H),3.32 (s, 3H); LCMS: purity: 83%, MS (m/e): 428 (MH+). 527N2,N4-Bis[3-methoxycarbonyl-5- (oxazol-2-yl)phenyl]-5-fluoro- 1H NMR(DMSO-d6): d 9.89 (s, 1H), 9.83 (s, 1H), 8.58 (s, 1H), 8.49 (s, +2,4-pyrimidinediamine 1H), 8.46 (s, 1H), 8.35 (s, 1H), 8.27 (d, 1H, J =3.6 Hz), 8.08 (m, 3H), 7.30 (s, 1H), 7.27 (s, 3H), 3.71 (s, 3H), 3.68(s, 3H); LCMS: purity: 86%, MS (M/e): 531 (MH+). 528 N2,N4-Bis(3,5-dimethylisoxazol-4-yl)-5-fluoro-2,4- 1H NMR (DMSO-d6): d 8.76 (s,1H), 8.13 (s, 1H), 7.83 (d, 1H, J = 3.9 − pyrimidinediamine Hz), 2.19(s, 3H), 2.10 (s, 3H), 2.03 (s, 3H), 1.85 (s, 3H); LCMS: purity: 91%, MS(m/e): 319 (MH+). 529 N2,N4-Bis[3-(oxazol-2-yl)-5-trifluoromethylphenyl]-5-fluoro-2,4- 1H NMR (DMSO-d6): d9.99 (s, 1H), 9.19 (s, 1H), 8.60 (s, 1H), 8.54 (s, + pyrimidinediamine1H), 8.31 (d, 1H, J = 2.7 Hz), 8.11 (d, 1H, J = 5.1 Hz), 8.05 (s, 1H),7.79 (s, 1H), 7.61 (s, 1H), 7.31 (s, 1H), 7.27 (s, 1H); LCMS: purity:92%, MS (m/e): 551 (MH+). 530 N2-[(2-tert-Butyl-1,3,4-oxadiazol-5-yl)phenyl]-N4- (3,4- 1H NMR (DMSO-d6): d9.43 (s, 1H), 9.23 (s, 1H), 8.25 (s, 1H), 8.08 + + +dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (d, 1H, J = 3.6 Hz),7.93 (bd, 1H, J = 8.7 Hz), 7.49 9bd, 1H, J = 7.5 Hz), 7.35 (m, 2H), 7.25(d, 1H, J = 2.4 Hz), 6.75 (d, 1H, J = 8.7 Hz), 3.70 (s, 3H), 3.66 (s,3H), 1.37 (s, 9H). 531 N2-[(2-tert-Butyl-1,3,4-oxadiazol-5-yl)phenyl]-N4- (3,4- 1H NMR (DMSO-d6): d9.45 (s, 1H), 9.19 (s, 1H), 8.25 (t, 1H, J = 1.8 +ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine Hz), 8.07 (d, 1H, J= 3.3 Hz), 7.87 (bd, 1H, J = 2.4 Hz), 7.51 (bd, 1H, J = 7.8 Hz), 7.40(m, 2H), 7.16 (dd, 1H, J = 2.4 and 8.7 Hz), 6.70 (d, 1H, J = 9 Hz), 4.15(m, 4H), 1.37 (s, 9H); LCMS: 532 N2-[(2-tert-Butyl-1,3,4-oxadiazol-5-yl)phenyl]-5-fluoro-N4- (3- 1H NMR(DMSO-d6): d 9.45 (s, 1H), 9.28 (s, 1H), 9.23 (s, 1H), 8.24 (s, +hydroxyphenyl)-2,4-pyrimidinediamine 1H), 8.11 (d, 1H, J = 3.9 Hz), 8.00(bd, 1H, J = 8.1 Hz), 7.50 (d, 1H, J = 7.8 Hz), 7.39 (t, 1H, J = 8.4Hz), 7.30 (bd, 1H, J = 8.4 Hz), 7.12 (t, 1H, J = 2.1 Hz), 6.99 (t, 1H, J= 8.4 Hz), 6. 533 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-methyl-2-hydrazine- 1H NMR(DMSO-d6): d 7.61 (d, 1H, J = 5.4 Hz), 6.86 (m, 1H), 6.69 (m, −4-pyrimidineamine 2H), 4.29 (s, 4H), 3.51 (s, 3H); LCMS: purity: 90%, MS(m/e): 292 (MH+). 534 N4- (3,5-Dimethylisoxazol-4-yl)-5-fluoro-N2-[3-(oxazol-2- 1H NMR (DMSO-d6): d 9.35 (s, 1H), 8.88 (s, 1H), 8.31 (s, 1H),8.14 (s, + yl)phenyl]-2,4-pyrimidinediamine 1H), 8.10 (d, 1H, J = 3.6Hz), 7.71 (bd, 1H, J = 7.8 Hz), 7.45 (d, 1H, J = 6.6 Hz), 7.32 (d, 1H, J= 0.9 Hz), 7.29 (t, 1H, J = 8.1 Hz), 2.87 (s, 3H), 2.10 (s, 3H); LCMS:purity: 96%, MS (m/ 535 N4- (3,5-Dimethylisoxazol-4-yl)-5-fluoro-N2-[5-LCMS: purity: 85%, MS (m/e): 425 (MH+). + methoxycarbonyl-3-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 536 N2-(3,5-Dimethyl-4-methoxyphenyl)-N4- (2,2-dimethyl-3-oxo- 1H NMR(DMSO-d6): d 11.16 (s, 1H), 10.00 (s, 1H), 9.52 (s, 1H), 8.16 −4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine p- (d, 1H, J= 4.2 Hz), 7.46 (m, 2H), 7.35 (d, 1H, J = 8.1 Hz), 7.13 (s, 2H), TolueneSulfonic Acid Salt 7.08 (d, 1H, J = 2.4 Hz), 3.60 (s, 3H), 2.28 (s, 3H),2.14 (s, 6H), 1.43 (s, 6H); LCMS: purity: 99%, MS (m/e): 439 537 N2-(3,5-Dimethyl-4-methoxyphenyl)-N4- (2,2-dimethyl-3-oxo- 1H NMR(DMSO-d6): d 11.19 (s, 1H), 10.52 (s, 1H), 9.65 (s, 1H), 8.19 −4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine (d, 1H, J =4.5 Hz), 7.56 (m, 2H), 7.44 (d, 1H, J = 8.4 Hz), 7.35 (d, 1H,Benzenesulfonic Acid Salt J = 8.4 Hz), 7.30 (m, 3H), 7.10 (s, 2H), 3.60(s, 3H), 2.14 (s, 6H), 1.43 (s, 6H); LCMS: purity: 93%, MS (m/e): 439538 N2- (3,5-Dimethyl-4-methoxyphenyl)-N4- (2,2-dimethyl-3-oxo- 1H NMR(DMSO-d6): d 11.80 (s, 1H), 10.16 (s, 1H), 9.73 (s, 1H), 8.21 −4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine (d, 1H, J =4.2 Hz), 7.44 (d, 1H, J = 8.4 Hz), 7.36 (d, 1H, J = 8.4 Hz),Methanesulfonic Acid Salt 7.12 (s, 2H), 3.60 (s, 3H), 2.32 (s, 3H), 2.13(s, 6H), 1.43 (s, 6H); LCMS: purity: 97%, MS (m/e): 439 (MH+, for par539 N4- (2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 10.67 (s, 1H), 10.60 (s, 1H), 10.05 (s, 1H), +(2-trifluoromethyl-3H-benzimidazol-5-yl)-2,4-pyrimidinediamine 8.20 (d,1H, J = 4.8 Hz), 7.84 (s, 1H), 7.62 (d, 1H, J = 9 Hz), 7.45 (bd,p-Toluenesulfonic Acid Salt 2H, J = 7.8 Hz), 7.23 (d, 1H, J = 8.7 Hz),7.15 (s, 1H), 7.09 (d, 1H, J = 7.8 Hz), 6.85 (d, 1H, J = 8.7 Hz), 2.28(s, 3H), 540 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 10.66 (s, 1H), 10.20 (s, 1H), 9.90 (s, 1H), 8.17 +(2-trifluoromethyl-3H-benzimidazol-5-yl)-2,4-pyrimidinediamine (d, 1H, J= 4.5 Hz), 7.88 (s, 1H), 7.57 (m, 3H), 7.48 (d, 1H, J = 8.4 Hz),Benzenesulfonic Acid Salt 7.29 (m, 4H), 7.15 (s, 1H), 6.85 (d, 1H), J =8.4 Hz); LCMS: purity: 95%, MS (m/e): MH+, for parent ion). 541 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 10.67 (s, 1H), 10.45 (s, 1H), 10.19 (s, 1H), +(2-trifluoromethyl-3H-benzimidazol-5-yl)-2,4-pyrimidinediamine 8.23 (d,1H, J = 5.1 Hz), 7.80 (s, 1H), 7.62 (d, 1H, J = 8.7 Hz), 7.45 (d,Methanesulfonic Acid Salt 1H, J = 8.4 Hz), 7.11 9s, 1H), 6.85 (d, 1H, J= 8.4 Hz), 2.38 (s, 3H), 1.37 (s, 6H); LCMS: purity: 99%, MS (m/e): 488(M 542 N4- (2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1HNMR (DMSO-d6): d 10.64 (s, 1H), 9.90 (s, 1H), 9.80 (s, 1H), 8.15 +(2-trifluoromethyl-3H-benzimidazol-5-yl)-2,4-pyrimidinediamine (d, 1H, J= 4.8 Hz), 7.96 (s, 1H), 7.59 (d, 1H, J = 8.7 Hz), 7.50 (dd, 1H,Hydrogen Chloride Salt J = 1.5 and 9.3 Hz), 7.25 (m, 2H), 6.87 (d, 1H, J= 8.4 Hz); LCMS: purity: 99%, MS (m/e): 488 (MH+, for parent ion). 543N4- (2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- LCMS:purity: 98%; MS (m/e): 470 (MH+); + + +(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 544 N4-(2-Amino-3-methoxy-pyrid-6-yl)-N2- (3,5-dimethoxyphenyl)- LCMS: purity:92%; MS (m/e): 387 (MH+) + 5-fluoro-2,4-pyrimidinediamine 545 N4-(2-Amino-3-methoxypyrid-6-yl)-5-fluoro-N2- (3,4,5- LCMS: purity: 94%; MS(m/e): 417 (MH+) + trimethoxyphenyl)-2,4-pyrimidinediamine 546 N4-(2-Amino-3-methoxypyrid-6-yl)-5-fluoro-N2- (2- LCMS: purity: 82%; MS(m/e): 425 (MH+) + methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine547 N4- (2-Amino-3-methoxypyrid-6-yl)-5-fluoro-N2[3- (N- LCMS: purity:89%; MS (m/e): 414 (MH+) + methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine 548 N2- (3,5-Dichloro-4-hydroxyphenyl)-N4-(3,5-dichloro-4- LCMS: purity: 92%; MS (m/e): 465 (MH+) + +methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 549 N4-(4-Acetyl-2,2-dimethyl-3-oxo-pyrid[1,4]oxazin-6-yl)-5- LCMS: purity:97%; MS (m/e): 513 (M+) fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 550 N4-Acetyl-N4-(2,2-dimethyl-3-oxo-4H-pyrid[1,4]oxazin-6-yl)-5- LCMS: purity: 96%; MS(m/e): 513 (M+) fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 551 N2-Acetyl-N4-(2,2-dimethyl-3-oxo-4H-pyrid[1,4]oxazin-6-yl)-5- LCMS: purity: 95%; 514(MH+) fluoro-N2- (3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 5522,N4-Bis[3-methyl-4- (4-methylpiperazinyl)phenyl)-5-fluoro-2,4- LCMS:purity: 99%; MS (m/e): 506 (MH+) pyrimidinediamine 553 N4-(3,5-Dimethylphenyl)-5-fluoro-N2- (3,4,5-trimethoxyphenyl)- ¹H NMR(DMSO-d6): d 9.14 (bs, 1H), 9.04 (s, 1H), 8.06 (d, J = 3.9 Hz, +2,4-pyrimidinediamine 1H), 7.40-7.36 (m, 2H), 6.95 (s, 2H), 6.67 (s,1H), 3.58-3.56 (m, 9H), 2.19 (s, 6H); LCMS: purity: 96%; MS (m/e): 399(MH+). 554 N2- (3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4- (3,5- ¹HNMR (DMSO-d6): d 9.21 (bs, 1H), 9.04 (bs, 1H), 8.63 (bs, 1H), +dimethylphenyl)-2,4-pyrimidinediamine 8.05 (d, J = 3.6 Hz, 1H),7.53-7.49 (m, 1H), 7.34-7.30 (m, 2H), 7.24- 7.20 (m, 1H), 6.69 (bs, 1H),2.22 (s, 6H), 2.09 (s, 3H); LCMS: purity: 93%; MS (m/e): 373 (MH+). 555N2-[3,5-Bis (hydroxymethylene)phenyl]-N4- (3,5- ¹H NMR (DMSO-d6): d 9.11(s, 2H), 8.06 (d, J = 3.9 Hz, 1H), 7.45 (s, +dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine 2H), 7.38 (s, 2H), 6.85(s, 1H), 6.68 (s, 1H), 4.38-4.34 (m, 4H), 2.22 (s, 6H); LCMS: purity:99%; MS (m/e): 369 (MH+). 556 N2- (3,5-Dichlorophenyl)-N4-(3,5-dimethylphenyl)-5-fluoro-2,4- ¹H NMR (DMSO-d6): d 9.76 (bs, 1H),9.51 (bs, 1H), 8.18 (d, J = 3.9 + + pyrimidinediamine Hz, 1H), 7.73-7.69(m, 2H), 7.29-7.25 (m, 2H), 7.04 (t, J = 1.8 Hz, 1H), 6.75 (s, 1H), 2.25(s, 6H); LCMS: purity: 92%; MS (m/e): 378 (MH+). 557 N4-(3,5-Dimethylphenyl)-5-fluoro-N2-[2- (N- ¹H NMR (DMSO-d6): d 11.66 (s,1H), 9.37 (s, 1H), 9.28 (s, 1H), 8.48- −methylamino)carbonylindol-7-yl]-2,4-pyrimidinediamine 8.40 (m, 1H), 8.13(d, J = 3.6 Hz, 1H), 7.98-7.88 (m, 1H), 7.33 (s, 2H), 7.22 (d, J = 7.8Hz, 1H), 7.04 (d, J = 1.8 Hz, 1H), 6.90 (t, J = 8.1 Hz. 1H), 6.71 (s,1H), 2.80 (d, J = 3.0 Hz, 3H), 2 558 5-Fluoro-N4-(3-methoxy-5-trifluoromethylphenyl)-N2-[2- (N- ¹H NMR (DMSO-d6): d 11.57(s, 1H), 9.65 (s, 1H), 9.40 (s, 1H), 8.39- +methylamino)carbonylindol-7-yl]-2,4-pyrimidinediamine 8.35 (m, 1H), 8.15(d, J = 3.9 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.73- 7.69 (m, 1H),7.57-7.52 (m, 1H), 7.18 (d, J = 7.8 Hz, 1H), 9.98 (d, J = 1.8 Hz, 1H),6.87-6.80 (m, 2H), 3.70 (s, 3H), 2. 559 N2-(3,5-Dichloro-4-hydroxyphenyl)-N4- (3,5-dimethylphenyl)-5- ¹H NMR(DMSO-d6): d 9.49 (s, 1H), 9.21 (s, 1H), 9.19 (s, 1H), 8.08 (d, + +fluoro-2,4-pyrimidinediamine J = 3.3 Hz, 1H), 7.66 (d, J = 1.5 Hz, 2H),7.29 (s, 2H), 6.70 (s, 1H), 2.24 (s, 6H); LCMS: purity: 95%; MS (m/e):394 (MH+). 560 N2- (4-Chloro-3,5-dimethylphenyl)-N4-(3,5-dimethylphenyl)-5- ¹H NMR (DMSO-d6): d 9.17 (s, 1H), 9.13 (s, 1H),8.07 (d, J = 3.9 Hz, − fluoro-2,4-pyrimidinediamine 1H), 7.45 (s, 2H),7.30 (s, 2H), 6.72 (s, 1H), 2.22 (s, 6H), 2.18 (s, 6H); LCMS: purity:93%; MS (m/e): 372 (MH+). 561 N4-[3,4-(Difluoromethylenedioxy)phenyl]-5-fluoro-N2- (3,4,5- ¹H NMR (DMSO-d6): d9.53 (s, 1H), 9.13 (s, 1H), 8.17-8.12 (m, 1H), +trimethoxyphenyl)-2,4-pyrimidinediamine 8.11 (d, J = 3.9 Hz, 1H), 7.42(dd, J = 2.4 and 9.0 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.00 (s, 2H),3.64 (s, 6H); 19F NMR (282 MHz, DMSO- d6): −49.77, −164.19; LCMS:purity: 93%; MS (m/e): 4 562 N4-[3,4-(Difluoromethylenedioxy)phenyl]-N2- (3,5- ¹H NMR (DMSO-d6): d 9.54 (s,1H), 9.22 (s, 1H), 8.12 (d, J = 3.6 Hz, + +dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 1H), 8.11-8.08 (m, 1H),7.42 (dd, J = 2.1 and 9.0 Hz, 1H), 7.32 (d, J = 8.7 Hz, 1H), 6.90 (d, J= 2.1 Hz, 2H), 6.07 (t, J = 2.4 Hz, 1H), 3.65 (s, 6H); 19F NMR (282 MHz,DMSO-d6): −49.69, −16 563 N4-[3,4- (Difluoromethylenedioxy)phenyl]-N2-(3,5- ¹H NMR (DMSO-d6): d 9.51 (s, 1H), 9.13 (s, 1H), 8.11 (d, J = 3.6Hz, + + dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine 1H), 8.09-8.06(m, 1H), 7.39 (dd, J = 2.1 and 8.7 Hz, 1H), 7.34 (d, J = 9.0 Hz, 1H),7.22 (s, 2H), 6.53 (s, 1H), 2.16 (s, 6H); 19F NMR (282 MHz, DMSO-d6):−49.67, −164.51; LCMS: purity: 98 564 N2-(3,5-Dichloro-4-hydroxyphenyl)-N4-[3,4- ¹H NMR (DMSO-d6): d 9.59 (s,1H), 9.45 (bs, 1H), 9.31 (s, 1H), 8.08 +(difluoromethylenedioxy)phenyl]-5-fluoro-2,4- (d, J = 3.6 Hz, 1H),7.85-7.79 (m, 1H), 7.55 (s, 1H), 7.29 (s, 1H); 19F pyrimidinediamine NMR(282 MHz, DMSO-d6): −49.50, −163.68; LCMS: purity: 96%; MS (m/e): 446(MH+). 565 N2- (3,5-Dichlorophenyl)-N4-[3,4- ¹H NMR (DMSO-d6): d9.62-9.68 (m, 2H), 8.19 (d, J = 3.6 Hz, 1H), +(difluoromethylenedioxy)phenyl]-5-fluoro-2,4- 7.92-7.88 (m, 1H), 7.71(s, 1H), 7.70 (s, 1H), 7.38-7.33 (m, 2H), 7.00 pyrimidinediamine (t, J =1.8 Hz, 1H); 19F NMR (282 MHz, DMSO-d6): −49.51, −162.64; LCMS: purity:99%; MS (m/e): 430 (MH+). 566 N2- (4-Chloro-3,5-dimethylphenyl)-N4-[3,4-¹H NMR (DMSO-d6): d 9.84 (s, 1H), 9.51 (s, 1H), 8.18 (s, J = 2.7 Hz, −(difluoromethylenedioxy)phenyl]-5-fluoro-2,4- 1H), 7.99 (bs, 1H),7.41-7.35 (m, 4H), 2.22 (s, 6H); LCMS: purity: 94%; pyrimidinediamine MS(m/e): 424 (MH+). 567 N2- (3-Chloro-4-hydroxy-5-methylphenyl)-N4-[3,4-¹H NMR (DMSO-d6): d 9.57 (s, 1H), 9.14 (s, 1H), 8.58 (bs, 1H), 8.05 +(difluoromethylenedioxy)phenyl]-5-fluoro-2,4- (d, J = 3.9 Hz, 1H), 7.90(s, 1H), 7.44 (d, J = 1.8 Hz, 1H), 7.31 (dd, J = pyrimidinediamine 1.8and 8.7 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.14-7.09 (m, 1H), 2.06 (s,3H); 19F NMR (282 MHz, DMSO-d6): −49.60, 568 N4-[3,4-(Difluoromethylenedioxy)phenyl]-5-fluoro-N2- (3- ¹H NMR (DMSO-d6): d9.60 (s, 1H), 9.56 (s, 1H), 8.17 (d, J = 3.3 Hz, −methoxy-5-trifluoromethylphenyl)-2,4-pyrimidinediamine 1H), 8.00 (s,1H), 7.66 (s, 1H), 7.52 (s, 1H), 7.41-7.31 (m, 2H), 6.72 (s, 1H), 3.74(s, 3H); 19F NMR (282 MHz, DMSO-d6): −49.75, −61.96, −162.93; LCMS:purity: 93%; MS (m/e): 459 (MH+). 569 N4-[3,4-(Difluoromethylenedioxy)phenyl]-5-fluoro-N2- (3- ¹H NMR (DMSO-d6): d9.66 (s, 1H), 9.59 (s, 1H), 8.19 (d, J = 3.6 Hz, +methyl-5-trifluoromethylphenyl)-2,4-pyrimidinediamine 1H), 8.04-7.97 (m,1H), 7.84 (bs, 1H), 7.68 (bs, 1H), 7.36 (bs, 2H), 7.03 (s, 1H), 2.29 (s,3H); 19F NMR (282 MHz, DMSO-d6): −49.63, −61.86, −163.10; LCMS: purity:98%; MS (m/e): 443 (MH 570 N4-[3,4-(Difluoromethylenedioxy)phenyl]-5-fluoro-N2-[2- (N- ¹H NMR (DMSO-d6): d11.56 (s, 1H), 9.63 (s, 1H), 9.34 (s, 1H), 8.44- +methylamino)carbonylindol-7-yl]-2,4-pyrimidinediamine 8.38 (m, 1H), 8.12(d, J = 3.6 Hz, 1H), 7.97 (bs, 1H), 7.84-7.78 (m, 1H), 7.38-7.32 (m,1H), 7.26 (d, J = 9.0 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.00 (s, 1H),6.87 (t, J = 7.8 Hz, 1H), 2.74 ( 571 N4-(3-Chloro-4-methoxyphenyl)-N2-[3,5-dimethyl-4- (N- ¹H NMR (DMSO-d6): d9.28 (s, 1H), 9.03 (s, 1H), 8.15-8.07 (m, 1H), + +methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4- 8.05 (d, J = 3.3Hz, 1H), 7.76-7.72 (m, 2H), 7.68-7.60 (m, 1H), 7.23 (s,pyrimidinediamine 2H), 7.09 (d, J = 9.0 Hz, 1H), 4.10 (s, 2H), 3.83 (s,3H), 2.69 (d, J = 4.2 Hz, 3H), 2.11 (s, 6H); LCMS: purity: 99%; 572N2-[3,5-dimethyl-4- (N- ¹H NMR (DMSO-d6): d 9.08 (s, 1H), 8.95 (s, 1H),8.14-8.06 (m, 1H), + + methylamino)carbonylmethyleneoxyphenyl]-N4- (3,4-8.00 (d, J = 3.6 Hz, 1H), 7.23-7.25 (m, 3H), 7.20-7.14 (m, 1H), 6.78 (d,ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine J = 8.7 Hz, 1H),4.21 (s, 4H), 4.11 (s, 2H), 2.69 (d, J = 4.5 Hz, 3H), 2.13 (s, 6H);LCMS: purity: 99%; MS (m/e): 454 573 N4-(3,5-Dimethoxyphenyl)-N2-[3,5-dimethyl-4- (N- ¹H NMR (DMSO-d6): d 9.20(s, 1H), 9.01 (s, 1H), 8.14-8.05 (m, 2H), + +methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4- 7.29 (s, 2H),7.00-6.96 (m, 2H), 6.24-6.19 (m, 1H), 4.11 (s, 2H), 3.67pyrimidinediamine (s, 6H), 2.70 (d, J = 4.8 Hz, 3H), 2.12 (s, 6H); LCMS:purity: 99%; MS (m/e): 456 (MH+). 574 N2-[3,5-dimethyl-4- (N- ¹H NMR(DMSO-d6): d 10.59 (s, 1H), 9.32 (s, 1H), 8.95 (s, 1H), 8.11- + +methylamino)carbonylmethyleneoxyphenyl]-N4- (2,2-dimethyl- 8.06 (m, 1H),8.04 (d, J = 3.9 Hz, 1H), 7.34-7.23 (m, 3H), 7.21-7.18 (m,3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 1H), 6.87(d, J = 9.0 Hz, 1H), 4.10 (s, 2H), 2.69 (d, J = 4.8 Hz, 3H), 2.11 (s,6H), 1.40 (s, 6H); LCMS: purity: 95%; 575 N2-[3,5-dimethyl-4- (N- ¹H NMR(DMSO-d6): d 9.15 (s, 1H), 8.96 (s, 1H), 8.12-8.05 (m, 1H), + +methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4- (3,4- 8.01 (d, J =3.9 Hz, 1H), 7.44-7.40 (m, 1H), 7.25 (s, 2H), 7.15-7.07 (m,methylenedioxyphenyl)-2,4-pyrimidinediamine 1H), 6.84 (d,J = 8.1 Hz,1H), 5.98 (s, 2H), 4.11 (s, 2H), 2.69 (d, J = 4.8 Hz, 3H), 2.13 (s, 6H);LCMS: purity: 99%; 576 2-Chloro-5-fluoro-N4-(2-isopropoxypyrid-5-yl)-N4-methyl-4- 1H NMR (DMSO-d6): d 8.17 (d, J =2.7 Hz, 1H), 8.14 (d, J = 5.4 Hz, − − pyrimidineamine 1H), 7.74 (dd, J =2.7 and 8.7 Hz, 1H), 6.77 (dd, J = 0.6 and 8.7 Hz, 1H), 5.21 (quintet, J= 6.3 Hz, 1H), 3.38 (s, 3H), 1.29 (d, J = 6.3 Hz, 6H); LCMS: purity:95%; MS (m/e): 298 (MH+). 577 N4- (3-Chloro-4-methoxyphenyl)-N2-(3,5-dimethoxyphenyl)-5- 1H NMR (DMSO-d6): d 7.95 (d, J = 5.7 Hz, 1H),7.46 (d, J = 2.7 Hz, + − fluoro-N4-methyl-2,4-pyrimidinediamine 1H),7.28 (dd, J = 2.4 and 9.0 Hz, 1H), 7.13 (d, J = 9.0 Hz, 1H), 6.98 (s,1H), 6.97 (s, 1H), 6.09-6.06 (m, 1H), 3.86 (s, 3H), 3.69 (s, 6H), 3.44(s, 3H); LCMS: purity: 96%; MS (m/e): 419 (MH+ 578 N2-(3-Chloro-4-methoxy-5-methylphenyl)-N4- (3-chloro-4- 1H NMR (DMSO-d6): d9.41 (s, 1H), 7.99 (d, J = 6.3 Hz, 1H), 7.69 (d, + −methoxyphenyl)-5-fluoro-N4-methyl-2,4-pyrimidinediamine J = 2.7 Hz, 1H),7.47 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 1.8 Hz, 1H), 7.28 (dd, J = 2.7and 8.7 Hz, 1H), 7.14 (d, J = 8.7 Hz, 1H), 3.87 (s, 3H), 3.68 (s, 3H),3.42 (s, 3H), 2.19 (s, 3H); LCMS: 579 N4-(3-Chloro-4-methoxyphenyl)-N2-[3,5-dimethyl-4- (N- 1H NMR (DMSO-d6): d9.24 (s, 1H), 8.16-8.04 (m, 1H), 7.96 (d, J = + −methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4- 6.0 Hz, 1H), 7.47(d, J = 2.4 Hz, 1H), 7.31-7.24 (m, 3H), 7.15 (d, J = 8.7methyl-2,4-pyrimidinediamine Hz, 1H), 4.12 (s, 2H), 3.87 (s, 3H), 3.42(s, 3H), 2.69 (d, J = 4.8 Hz, 3H), 2.15 (s, 6H); LCMS: purity: 92%; MS(m/e 580 N4- (3-Chloro-4-methoxyphenyl)-N2-[3- (N- 1H NMR (DMSO-d6): d9.63 (bs, 1H), 8.02 (d, J = 6.3 Hz, 1H), 8.00- + −methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4- 7.97 (m, 1H), 7.50(d, J = 2.7 Hz, 1H), 7.36-7.34 (m, 1H), 7.33-7.20 (m,methyl-2,4-pyrimidinediamine 3H), 7.16 (d, J = 9.0 Hz, 2H), 6.57-6.52(m, 1H), 4.41 (s, 2H), 3.87 (s, 3H), 3.44 (s, 3H), 2.64 (d, J = 4.8 Hz,3H); L 581 N2- (3,5-Dimethoxyphenyl)-5-fluoro-N4- (2-isopropoxypyrid-5-1H NMR (DMSO-d6): d 9.47 (bs, 1H), 8.14 (d, J = 2.7 Hz, 1H), 7.99 (d, +− yl)-N4-methyl-2,4-pyrimidinediamine J = 6.0 Hz, 1H), 7.71 (dd, J = 3.0and 8.7 Hz, 1H), 6.96-6.93 (m, 2H), 6.77 (dd, J = 0.6 and 8.7 Hz, 1H),6.12 (t, J = 2.1 Hz, 1H), 5.21 (quintet, J = 6.3 Hz, 1H), 3.70 (s, 6H),3.45 (s, 3H) 582 5-Fluoro-N4- (2-isopropoxypyrid-5-yl)-N4-methyl-N2-[3-(N- 1H NMR (DMSO-d6): d 9.53 (s, 1H), 8.14 (d, J = 3.0 Hz, 1H), 8.02- +− methylamino)carbonylmethyleneoxyphenyl]-2,4- 7.93 (m, 2H), 7.70 (dd, J= 2.7 and 8.7 Hz, 1H), 7.37 (t, J = 2.1 Hz, 1H), pyrimidinediamine7.26-7.20 (m, 1H), 7.13 (t, J = 8.1 Hz, 1H), 6.78 (d, J = 8.7 Hz, 1H),6.56-6.50 (m, 1H), 5.22 (quintet, J = 6.0 Hz, 1H) 583 N2-(3,5-Dimethylphenyl)-5-fluoro-N4- (2-isopropoxypyrid-5-yl)- 1H NMR(DMSO-d6): d 9.42 (s, 1H), 8.14 (d, J = 2.7 Hz, 1H), 8.01 (d, + −N4-methyl-2,4-pyrimidinediamine J = 6.6 Hz, 1H), 3.45 (s, 3H), 2.19 (s,6H), 1.29 (d, J = 6.3 Hz, 6H), 7.70 (dd, J = 2.7 and 8.7 Hz, 1H), 7.24(s, 2H), 6.77 (d, J = 8.4 Hz, 1H), 6.57 (s, 1H), 5.22 (quintet, J = 6.3Hz, 1H); 584 N4- (3-Chloro-4-methoxyphenyl)-N2- (3,5-dimethylphenyl)-5-1H NMR (DMSO-d6): d 9.09 (s, 1H), 7.94 (d, J = 6.0 Hz, 1H), 7.45 (d, + −fluoro-N4-methyl-2,4-pyrimidinediamine J = 2.1 Hz, 1H), 7.31-7.23 (m,3H), 7.13 (d, J = 9.0 Hz, 1H), 6.51 (s, 1H), 3.86 (s, 3H), 3.42 (s, 3H),2.18 (s, 6H); LCMS: purity: 88%; MS (m/e): 387 (MH+). 585 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2- (2- 1H NMR (DMSO-d6): d 9.45 (s,1H), 8.16 (d, J = 1.8 Hz, 1H), 8.05 (d, − −methoxycarbonylbenzofuran-5-yl)-N4-methyl-2,4- J = 6.0 Hz, 1H), 7.68(dd, J = 2.1 and 9.0 Hz, 1H), 7.65 (d, J = 0.9 Hz, pyrimidinediamine1H), 7.63-7.57 (m, 1H), 7.54 (d, J = 2.7 Hz, 1H), 7.35 (dd, J = 2.7 and8.7 Hz, 1H), 7.23 (d, J = 8.7 Hz, 1H), 3.95 (s, 586 5-Fluoro-N4-(2-isopropoxypyrid-5-yl)-N2- (2- 1H NMR (DMSO-d6): d; 9.39 (s, 1H), 8.13(d, J = 2.4 Hz, 1H), 8.09 (d, + +methoxycarbonylbenzofuran-5-yl)-N4-methyl-2,4- J = 1.8 Hz, 1H), 7.98 (d,J = 6.3 Hz, 1H), 7.70 (dd, J = 3.0 and 8.7 Hz, pyrimidinediamine 1H),7.64-7.57 (m, 2H), 7.54 (d, J = 8.7 Hz, 1H), 6.79 (d, J = 8.7 Hz, 1H),5.22 (quintet, J = 6.3 Hz, 1H), 3.87 (s, 587 N4-(4-Chloro-3-methoxyphenyl)-N2- (3,5-dimethoxyphenyl)-5- 1H NMR(DMSO-d6): d 9.44 (bs, 1H), 8.03 (d, J = 6.0 Hz, 1H), 7.40 (d, + + −fluoro-N4-methyl-2,4-pyrimidinediamine J = 8.1 Hz, 1H), 7.15 (d, J = 2.1Hz, 1H), 6.95 (d, J = 1.2 Hz, 2H), 6.90 (dd, J = 2.1 and 8.4 Hz, 1H),6.12-6.08 (m, 1H), 3.82 (s, 3H), 3.69 (s, 6H), 3.49 (s, 3H); LCMS:purity: 96%; MS (m 588 N4- (4-Chloro-3-methoxyphenyl)-N2-(3,5-dimethylphenyl)-5- 1H NMR (DMSO-d6): d 9.35 (bs, 1H), 8.03 (d, J =6.0, 1H), 7.41 (d, J = + − fluoro-N4-methyl-2,4-pyrimidinediamine 8.4,1H), 7.26-7.23 (m, 2H), 7.16 (d, J = 2.4 Hz, 1H), 6.90 (dd, J = 2.1 and8.7 Hz, 1H), 6.58-6.55 (m, 1H), 3.82 (s, 3H), 3.49 (s, 3H), 2.19 (s,6H); LCMS: purity: 91%; MS (m/e): 387 (MH+ 589 N4-(4-Chloro-3-methoxyphenyl)-5-fluoro-N4-methyl-N2-[3- (N- 1H NMR(DMSO-d6): d 9.34 (s, 1H), 8.00 (d, J = 5.4, 1H), 7.93-8.00 + + −methylamino)carbonylmethyleneoxyphenyl]-2,4- (m, 1H), 7.44 (t, J = 1.8Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.26 (dd, J = pyrimidinediamine 1.2and 8.4 Hz, 1H), 7.15-7.12 (m, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.87 (dd,J = 2.1 and 9.0 Hz, 1H), 6.47 (dd, J = 2.7 590 N4-(4-Chloro-3-methoxyphenyl)-5-fluoro-N2- (indol-5-yl)-N4- 1H NMR(DMSO-d6): d 10.84 (s, 1H), 9.010 (s, 1H), 7.96 (d, J = 5.4 + + −methyl-2,4-pyrimidinediamine Hz, 1H), 7.87-7.84 (m, 1H), 7.39 (d, J =8.1 Hz, 1H), 7.27-7.19 (m, 3H), 7.12 (d, J = 2.1 Hz, 1H), 6.87 (dd, J =2.4 and 8.7 Hz, 1H), 6.29-6.25 (m, 1H), 3.82 (s, 3H), 3.47 (s, 3H);LCMS: puri 591 N4- (4-Chloro-3,5-dimethylphenyl)-N2-(3,5-dimethoxyphenyl)- 1H NMR (DMSO-d6): d 9.51 (bs, 1H), 8.03 (d, J =6.0 Hz, 1H), 7.19 (s, + + − 5-fluoro-N4-methyl-2,4-pyrimidinediamine2H), 6.93 (d, J = 1.8 Hz, 2H), 6.12 (t, J = 2.4 Hz, 1H), 3.70 (s, 6H),3.46 (s, 3H), 2.32 (s, 6H); LCMS: purity: 98%; MS (m/e): 418 (MH+). 592N4- (4-Chloro-3,5-dimethylphenyl)-N2- (3,5-dimethylphenyl)-5- 1H NMR(DMSO-d6): d 9.49 (bs, 1H), 8.04 (d, J = 6.0 Hz, 1H), 7.24 (s, − −fluoro-N4-methyl-2,4-pyrimidinediamine 2H), 7.20 (s, 2H), 6.60 (s, 1H),3.45 (s, 3H), 2.32 (s, 6H), 2.19 (s, 6H); LCMS: purity: 98%; MS (m/e):386 (MH+). 593 N4-(4-Chloro-3,5-dimethylphenyl)-5-fluoro-N4-methyl-N2-[3- 1H NMR(DMSO-d6): d 9.32 (s, 1H), 7.98 (d, J = 5.7 Hz, 1H), 8.00- + + −(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- 7.92 (m, 1H), 7.44 (t, J= 2.1 Hz, 1H), 7.29-7.23 (m, 1H), 7.16 (s, 2H), pyrimidinediamine 7.10(t, J = 8.1 Hz, 1H), 6.47 (dd, J = 2.4 and 7.8 Hz, 1H), 4.39 (s, 2H),3.44 (s, 3H), 2.64 (d, J = 4.5 Hz, 3H), 2.32 ( 594 N4-(4-Chloro-3,5-dimethylphenyl)-5-fluoro-N2- (indol-5-yl)-N4- 1H NMR(DMSO-d6): d 10.84 (s, 1H), 8.98 (s, 1H), 7.94 (d, J = 5.7 Hz, + + +methyl-2,4-pyrimidinediamine 1H), 7.84 (s, 1H), 7.29-7.19 (m, 3H), 7.15(s, 2H), 6.26 (t, J = 2.1 Hz, 1H), 3.42 (s, 3H), 2.32 (s, 6H); LCMS:purity: 94%; MS (m/e): 397 (MH+). 595 N4-(4-Chloro-3,5-dimethylphenyl)-5-fluoro-N2- (2- 1H NMR (DMSO-d6): d 9.43(s, 1H), 8.17 (d, J = 1.8 Hz, 1H), 8.01 (d, − −methoxycarbonyl-benzofuran-5-yl)-N4-methyl-2,4- J = 5.4 Hz, 1H),7.68-7.61 (m, 2H), 7.55 (d, J = 9.3 Hz, 1H), 7.17 (s, pyrimidinediamine2H), 3.87 (s, 3H), 3.45 (s, 3H), 2.32 (s, 6H), ; LCMS: purity: 97%; MS(m/e): 457 (MH+). 596 N4-(4-Chloro-3,5-dimethylphenyl)-5-fluoro-N4-methyl-N2-[4- 1H NMR(DMSO-d6): d 9.66 (s, 1H), 8.11 (d, J = 0.90 Hz, 1H), 8.04 (d, − −(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine J = 5.4 Hz, 1H), 7.81 (s,4H), 7.28 (d, J = 0.6 Hz, 1H), 7.18 (s, 2H), 3.46 (s, 3H), 2.33 (s, 6H);LCMS: purity: 89%; MS (m/e): 425 (MH+). 597 N4-(4-Chloro-3,5-dimethylphenyl)-5-fluoro-N4-methyl-N2-[3- 1H NMR(DMSO-d6): d 9.71 (s, 1H), 8.40 (s, 1H), 8.24-8.18 (m, 1H), + −(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 8.06 (d, J = 6.0 Hz, 1H),7.59-7.53 (m, 2H), 7.34-7.29 (m, 2H), 7.20 (s, 2H), 3.49 (s, 3H), 2.32(s, 6H); LCMS: purity: 96%; MS (m/e): 425 (MH+). 598 N4-(4-Chloro-3,5-dimethylphenyl)-5-fluoro-N4-methyl-N2-[4- 1H NMR(DMSO-d6): d 9.64 (s, 1H), 8.35 (s, 1H), 8.04 (d, J = 5.7 Hz, + −(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 1H), 7.76 (d, J = 8.7 Hz,2H), 7.57 (d, J = 8.7 Hz, 2H), 7.49 (s, 1H), 7.19 (s, 2H), 3.46 (s, 3H),2.32 (s, 6H); LCMS: purity: 96%; MS (m/e): 425 (MH+). 599 N4-(4-Chloro-3,5-dimethylphenyl)-5-fluoro-N2- (indol-6-yl)-N4- 1H NMR(DMSO-d6): d 11.00 (s, 1H), 9.58 (bs, 1H), 8.00 (d, J = 6.0 + −methyl-2,4-pyrimidinediamine Hz, 1H), 7.89 (s, 1H), 7.41 (d, J = 8.4 Hz,1H), 7.24-7.18 (m, 3H), 7.11 (dd, J = 1.8 and 8.4 Hz, 1H), 6.35-6.31 (m,1H), 3.47 (s, 3H), 2.33 (s, 6H); LCMS: purity: 95%; MS (m/e): 397 (MH+).600 N4-[3-Chloro-4- (N- 1H NMR (DMSO-d6): d 9.94 (bs, 1H), 9.65 (bs,1H), 8.18 (d, J = 4.2 + + − methylamino)carbonylmethyleneoxyphenyl]-N2-(3,5- Hz, 1H), 7.93-7.84 (m, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.66 (dd, J= 2.7 dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine and 9.0 Hz, 1H),7.12 (s, 2H), 6.99 (d, J = 9.0 Hz, 1H), 6.64 (s, 1H), 4.55 (s, 2H), 2.66(d, J = 4.8 Hz, 3H), 2.18 (s, 601 N4-[3-Chloro-4- (N- 1H NMR (DMSO-d6):d 9.52 (bs, 1H), 9.30 (bs, 1H), 8.11 (d, J = 3.9 + + −methylamino)carbonylmethyleneoxyphenyl]-N2- (3,5- Hz, 1H), 7.92-7.85 (m,1H), 7.79 (d, J = 2.4 Hz, 1H), 7.74 (dd, J = 2.7dimethoxylphenyl)-5-fluoro-2,4-pyrimidinediamine and 8.7 Hz, 1H), 6.96(d, J = 9.0 Hz, 1H), 6.85 (d, J = 1.8 Hz, 2H), 6.10 (t, J = 2.4 Hz, 1H),4.54 (s, 2H), 3.64 (s, 6H) 602 N2-(3-Chloro-4-methoxyphenyl)-N4-[3-chloro-4- (N- 1H NMR (DMSO-d6): d 9.45(bs, 1H), 9.25 (bs, 1H), 8.03 (d, J = 3.3 + + −methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4- Hz, 1H), 7.86-7.78(m, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.64 (d, J = 2.4 Hz,pyrimidinediamine 1H), 7.58 (dd, J = 2.7 and 9.3 Hz, 1H), 6.96 (d, J =9.3 Hz, 1H), 6.93 (d, J = 9.3 Hz, 1H), 4.48 (s, 2H), 3.73 (s, 3H) 603N2- (4-Chloro-3,5-dimethylphenyl)-N4-[3-chloro-4- (N- 1H NMR (DMSO-d6):d 9.45 (bs, 1H), 9.2 = 8 (bs, 1H), 8.11 (d, J = 3.9 + − −methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4- Hz, 1H), 7.92-7.87(m, 1H), 7.75 (d, J = 2.4, 1H), 7.68 (dd, J = 2.7 and pyrimidinediamine9.3 Hz, 1H), 7.40 (s, 2H), 6.99 (d, J = 8.7 Hz, 1H), 4.54 (s, 2H), 2.67(d, J = 4.2 Hz, 3H), 2.22 (s, 6H), ; LCMS: pur 604 N4-(4-Chloro-3,5-dimethylphenyl)-5-fluoro-N4-methyl-N2-[4- 1H NMR(DMSO-d6): d 9.42 (s, 1H), 8.46-8.43 (m, 1H), 8.39-8.37 (m, + −(oxazol-4-yl)phenyl]-2,4-pyrimidinediamine 1H), 8.00 (d, J = 5.4 Hz,1H), 7.73 (d, J = 9.0 Hz, 2H), 7.62 (d, J = 9.0 Hz, 2H), 7.17 (s, 2H),3.45 (s, 3H), 2.32 (s, 6H); LCMS: purity: 96%; MS (m/e): 424 (MH+). 605N4-[3-Chloro-4- (N- 1H NMR (DMSO-d6): d 10.80 (s, 1H), 9.26 (s, 1H),9.07 (s, 1H), 8.06 + + −methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N2- (indol- (s, J = 3.9Hz, 1H), 7.93-7.75 (m, 4H), 7.36 (d, J = 8.4 Hz, 1H), 7.22-6-yl)-2,4-pyrimidinediamine 7.15 (m, 2H), 6.95 (d, J = 8.7 Hz, 1H),6.33-6.27 (m, 1H), 4.54 (s, 2H), 2.67 (d, J = 4.2 Hz, 3H); LCMS: purity:96%; M 606 N4- (4-Chloro-3-methoxyphenyl)-5-fluoro-N4-methyl-N2-[4- 1HNMR (DMSO-d6): d 9.44 (s, 1H), 8.44 (d, J = 0.90 Hz, 1H), 8.38 (d, + + +(oxazol-4-yl)phenyl]-2,4-pyrimidinediamine J = 0.90 Hz, 1H), 8.02 (d, J= 5.7 Hz, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.63 (d, J = 8.7 Hz, 2H), 7.41(d, J = 8.4 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 6.92-6.86 (m, 1H), 3.83(s, 3H), 3.49 (s, 3 607 N4- (4-Chloro-3-methoxyphenyl)-N2-[4-chloro-3-(N- 1H NMR (DMSO-d6): d 9.70 (bs, 2H), 8.23-8.18 (m, 1H), 8.15 (d, J= + + − methylamino)carbonylphenyl]-5-fluoro-2,4-pyrimidinediamine 4.2Hz, 1H), 7.71 (d, J = 2.7 Hz, 1H), 7.54 (dd, J = 2.7 and 9.0 Hz, 1H),7.45 (dd, J = 2.4 and 8.7 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.28 (d, J= 8.7 Hz, 1H), 7.24 (d, J = 9.0 Hz, 1H), 3.73 (s 608 N4-[3-Chloro-4- (N-1H NMR (DMSO-d6): d 9.53 (bs, 1H), 9.49 (bs, 1H), 8.28-8.21 (m, + −methylamino)carbonylmethyleneoxyphenyl]-N2-[4-chloro-3- (N- 1H), 8.13(d, J = 3.9 Hz, 1H), 7.93-7.87 (m, 1H), 7.77-7.64 (m, 4H),methylamino)carbonylphenyl]-5-fluoro-2,4-pyrimidinediamine 7.28 (d, J =8.7 Hz, 1H), 6.98 (d, J = 9.0 Hz, 1H), 4.59 (s, 2H), 2.70 (d, J = 4.8Hz, 3H), 2.67 (d, J = 4.5 Hz, 3H); LCMS: pu 609 N2-[4-Chloro-3-(N-methylamino)carbonylphenyl]-N4- (4-chloro- 1H NMR (DMSO-d6): d 9.84(s, 1H), 9.59 (s, 1H), 8.35-8.27 (m, 2H), + + −3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine 8.23 (d, J = 3.9Hz, 1H), 8.06 (d, J = 2.7 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.67-7.60(m, 2H), 7.29 (d, J = 9.0 Hz, 1H), 2.71 (d, J = 4.5 Hz, 3H); LCMS:purity: 92%; MS (m/e): 475 (MH+). 610 N4-(4-Chloro-3,5-dimethylphenyl)-N2-[4-chloro-3- (N- 1H NMR (DMSO-d6): d9.55 (s, 1H), 8.30-8.24 (m, 1H), 8.01 (d, J = − −methylamino)carbonylphenyl]-5-fluoro-N4-methyl-2,4- 6.6 Hz, 1H), 7.86(d, J = 2.7 Hz, 1H), 7.68 (dd, J = 2.7 and 9.0 Hz, 1H),pyrimidinediamine 7.27 (d, J = 8.7 Hz, 1H), 7.16 (s, 2H), 3.42 (s, 3H),2.72 (d, J = 4.5 Hz, 3H), 2.32 (s, 6H); LCMS: purity: 98%; MS (m/ 611N4- (4-Chloro-3-methoxyphenyl)-N2-[3-chloro-4- (N- 1H NMR (DMSO-d6): d9.57 (s, 1H), 9.54 (s, 1H), 8.19 (d, J = 3.6 Hz, + + −methylamino)carbonylphenyl]-5-fluoro-2,4-pyrimidinediamine 1H),8.15-8.08 (m, 1H), 7.93 (d, J = 2.1 Hz, 1H), 7.51 (dd, J = 2.4 and 8.7Hz, 1H), 7.47 (dd, J = 2.45 and 8.7 Hz, 1H), 7.43 (d, J = 2.1 Hz, 1H),7.34 (d, J = 8.7 Hz, 1H), 7.27 (d, J = 8.4 Hz 612 N2-[3-Chloro-4-(N-methylamino)carbonylphenyl]-N4- (4-chloro- 1H NMR (DMSO-d6): d 9.83(s, 1H), 9.65 (s, 1H), 8.33-8.26 (m, 1H), + + −3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine 8.25 (d, J = 3.6Hz, 1H), 8.16-8.11 (m, 1H), 8.06 (d, J = 2.7 Hz, 1H), 7.87 (d, J = 1.8Hz, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.52 (dd, J = 1.8 and 8.4 Hz, 1H),7.28 (d, J = 8.4 Hz, 1H), 2.72 (d, 613 N4-(4-Chloro-3,5-dimethylphenyl)-N2-[3-chloro-4- (N- 1H NMR (DMSO-d6): d9.66 (s, 1H), 8.17-8.09 (m, 1H), 8.05 (d, J = + −methylamino)carbonylphenyl]-5-fluoro-N4-methyl-2,4- 5.4 Hz, 1H), 7.94(d, J = 2.1 Hz, 1H), 7.54 (dd, J = 2.1 and 8.4 Hz, 1H),pyrimidinediamine 7.28 (d, J = 8.1 Hz, 1H), 7.18 (s, 2H), 3.44 (s, 3H),2.71 (d, J = 4.5 Hz, 3H), 2.32 (s, 6H); LCMS: purity: 99%; MS (m/ 614N4-[3-Chloro-4- (methoxycarbonyl)methyleneoxyphenyl]-N2- 1H NMR(DMSO-d6): d 10.28 (s, 1H), 10.05 (s, 1H), 8.26 (d, J = 4.8 + + +(3,5-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine Hz, 1H), 7.74 (d, J= 2.7 Hz, 1H), 7.57 (dd, J = 2.7 and 8.7 Hz, 1H), 7.10-7.01 (m, 3H),6.69 (s, 1H), 4.93 (s, 2H), 3.70 (s, 3H), 2.17 (s, 6H); LCMS: purity:98%; MS (m/e): 431 (MH+). 615 N4-[3-Chloro-4-(methoxycarbonyl)methyleneoxyphenyl]-N2- 1H NMR (DMSO-d6): d 9.75 (s,1H), 9.53 (s, 1H), 8.15 (d, J = 4.5 Hz, + + +(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 1H), 7.80 (d, J =2.7 Hz, 1H), 7.66 (dd, J = 2.7 and 9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz,1H), 6.81 (d, J = 2.4 Hz, 1H), 6.14 (t, J = 2.1 Hz, 1H), 4.90 (s, 2H),3.71 (s, 3H), 3.64 (s, 6H); LCMS: 616 N4-[3-Chloro-4-(methoxycarbonyl)methyleneoxyphenyl]-N2- (3- 1H NMR (DMSO-d6): d 9.63(s, 1H), 9.41 (s, 1H), 8.12 (d, J = 4.2 Hz, + + +chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 1H), 7.76 (d, J =2.7 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.60 (dd, J = 2.4 and 9.0 Hz,1H), 7.44 (dd, J = 2.7 and 8.7 Hz, 1H), 7.04 (d, J = 8.7 Hz, 1H), 7.02(d, J = 9.0 Hz, 1H), 4.90 (s, 2H), 617 N2-(4-Chloro-3,5-dimethylphenyl)-N4-[3-chloro-4- 1H NMR (DMSO-d6): d 9.64(s, 1H), 9.45 (s, 1H), 8.14 (d, J = 4.2 Hz, + + +(methoxycarbonyl)methyleneoxyphenyl]-5-fluoro-2,4- 1H), 7.75 (d, J = 2.4Hz, 1H), 7.61 (dd, J = 2.4 and 9.0 Hz, 1H), 7.38 (s, pyrimidinediamine2H), 7.02 (d, J = 9.0 Hz, 1H), 4.91 (s, 2H), 3.70 (s, 3H), 2.21 (s, 6H);LCMS: purity: 95%; MS (m/e): 465 (M+). 618 N4-[3-Chloro-4-(methoxycarbonyl)methyleneoxyphenyl]-5- 1H NMR (DMSO-d6): d 10.86 (s,1H), 9.23 (s, 1H), 8.94 (s, 1H), 8.03 + + − fluoro-N2-(indol-5-yl)-2,4-pyrimidinediamine (d, J = 3.9 Hz, 1H), 7.83 (d, J = 2.4Hz, 1H), 7.79 (s, 1H), 7.68 (dd, J = 2.4 and 9.0 Hz, 1H), 7.25-7.21 (m,3H), 6.93 (d, J = 9.0 Hz, 1H), 6.27 (t, J = 2.4 Hz, 1H), 4.89 (s, 2H),3.71 (s, 3 619 N4-[3-Chloro-4- (2-hydroxyethyleneoxy)phenyl]-N2- (3,5-1H NMR (DMSO-d6): d 9.63 (bs, 1H), 9.34 (bs, 1H), 8.11 (d, J = 4.2 + + +dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine Hz, 1H), 7.72 (d, J = 2.7Hz, 1H), 7.64 (dd, J = 2.7 and 9.0 Hz, 1H), 7.12 (d, J = 8.7 Hz, 1H),6.58 (s, 1H), 4.05 (t, J = 5.1 Hz, 2H), 3.73 (t, J = 5.1 Hz, 2H), 2.16(s, 6H), ; LCMS: purity: 9 620 N4-[3-Chloro-4-(2-hydroxyethyleneoxy)phenyl]-N2- (3,5- 1H NMR (DMSO-d6): d 9.29 (s,1H), 9.13 (s, 1H), 8.08 (d, J = 3.6 Hz, + + +dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 1H), 7.75 (d, J = 2.7Hz, 1H), 7.71 (dd, J = 2.7 and 8.7 Hz, 1H), 7.08 (d, J = 9.0 Hz, 1H),6.90 (d, J = 2.1 Hz, 2H), 6.05 (t, J = 2.1 Hz, 1H), 4.89 (t, J = 5.1 Hz,1H), 4.05 (t, J = 5.1 Hz, 2H 621 N4-[3-Chloro-4-(2-hydroxyethyleneoxy)phenyl]-N2- (3-chloro-4- 1H NMR (DMSO-d6): d 9.29(s, 1H), 9.15 (s, 1H), 8.06 (d, J = 3.6 Hz, + + −methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 1H), 7.74 (d, J = 2.1 Hz,2H), 7.63 (dd, J = 2.7 and 9.0 Hz, 1H), 7.46 (dd, J = 2.7 and 9.0 Hz,1H), 7.10 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 1H), 4.87 (t, J =5.4 Hz, 1H), 4.05 (t, J = 5 622 N2-(4-Chloro-3,5-dimethylphenyl)-N4-[3-chloro-4- (2- 1H NMR (DMSO-d6): d9.31 (s, 1H), 9.18 (s, 1H), 8.08 (d, J = 3.9 Hz, + + −hydroxyethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine 1H), 7.72 (d,J = 2.7 Hz, 1H), 7.63 (dd, J = 2.4 and 9.0 Hz, 1H), 7.42 (s, 2H), 7.12(d, J = 9.0 Hz, 1H), 4.87 (t, J = 5.7 Hz, 1H), 4.04 (t, J = 5.1 Hz, 2H),3.73 (q, J = 5.1 Hz, 2H), 2.20 (s, 623 N4-[3-Chloro-4-(2-hydroxyethyleneoxy)phenyl]-5-fluoro-N2- 1H NMR (DMSO-d6): d 10.84 (s,1H), 9.17 (s, 1H), 8.90 (s, 1H), 8.01 + + +(indol-5-yl)-2,4-pyrimidinediamine (d, J = 3.9 Hz, 1H), 7.82-7.76 (m,2H), 7.67 (dd, J = 3.0 and 9.3 Hz, 1H), 7.25-7.21 (m, 3H), 7.03 (d, J =9.0 Hz, 1H), 6.28-6.25 (m, 1H), 4.87 (t, J = 5.4 Hz, 1H), 4.04 (t, J =5.1 Hz, 2H), 624 N4-[3-Chloro-4- (2-hydroxyethyleneoxy)phenyl]-N2-(4-chloro-3- 1H NMR (DMSO-d6): d 9.49 (s, 1H), 9.42 (s, 1H), 8.12 (d, J= 3.9 Hz, + + − methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 1H), 7.80(d, J = 2.4 Hz, 1H), 7.59 (dd, J = 2.7 and 9.0 Hz, 1H), 7.40- 7.36 (m,1H), 7.30 (dd, J = 2.7 and 8.4 Hz, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.12(d, J = 8.7 Hz, 1H), 4.06 (t, J = 4.8 Hz, 625 N4-[3-Chloro-4- (N- 1H NMR(DMSO-d6): d 10.84 (s, 1H), 9.20 (s, 1H), 8.91 (s, 1H), 8.02 + + +methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N2- (indol- (d, J = 3.9Hz, 1H), 7.90-7.82 (m, 2H), 7.73 (dd, J = 2.4 and 9.0 Hz,5-yl)-2,4-pyrimidinediamine 1H), 7.26-7.19 (m, 3H), 6.93 (d, J = 8.7 Hz,1H), 6.28 (t, J = 2.4 Hz, 1H), 4.52 (s, 2H), 2.67 (d, J = 4.5 Hz, 3H);LCMS 626 2-Chloro-N4- (4-chloro-3,5-dimethylphenyl)-5-fluoro-N4-methyl-1H NMR (DMSO-d6): d 8.17 (d, J = 5.1 Hz, 1H), 7.23 (s, 2H), 3.38 (s, − +4-pyrimidineamine 3H), 2.32 (s, 6H); LCMS: purity: 98%; MS (m/e): 301(MH+). 627 2-Chloro-5-fluoro-N4-methyl-N4-[3,4- 1H NMR (DMSO-d6): d 7.94(d, J = 4.8 Hz, 1H), 7.17 (d, J = 9.6 Hz, − −(tetrafluoroethylenedioxy)phenyl]-4-pyrimidineamine 1H), 7.17 (d, J =9.6 Hz, 1H), 7.05-7.00 (m, 2H), 3.50 (s, 3H); LCMS: purity: 92%; MS(m/e): 368 (MH+). 628 2-Chloro-N4-[3,4-(difluoromethylenedioxy)phenyl]-5-fluoro-N4- 1H NMR (DMSO-d6): d 7.82(d, J = 4.5 Hz, 1H), 6.98 (d, J = 8.4 Hz, − − methyl-4-pyrimidineamine1H), 6.90-6.83 (m, 2H), 3.40 (s, 3H); LCMS: purity: 100%; MS (m/e): 318(MH+). 629 N4- (4-Chloro-3-trifluoromethylphenyl)-5-fluoro-N2-(indol-6-yl)- 1H NMR (DMSO-d6): d 10.86 (s, 1H), 9.67 (s, 1H), 9.14 (s,1H), 8.44 + + − 2,4-pyrimidinediamine (dd, J = 2.4 and 9.0 Hz, 1H), 8.15(d, J = 3.9 Hz, 1H), 8.12 (d, J = 2.7 Hz, 1H), 7.77 (s, 1H), 7.51 (d, J= 9.3 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.19 (t, J = 2.1 Hz, 1H), 7.14(dd, J = 1.8 a 630 N4- (4-Chloro-3-methoxyphenyl)-5-fluoro-N2-(indol-6-yl)-2,4- 1H NMR (DMSO-d6): d 10.85 (s, 1H), 9.35 (s, 1H), 9.04(s, 1H), 8.10 + + − pyrimidinediamine (d, J = 3.6 Hz, 1H), 7.79 (s, 1H),7.62-7.57 (m, 2H), 7.36 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 9.0 Hz, 1H),7.19 (t, J = 2.7 Hz, 1H), 7.15 (dd, J = 1.8 and 8.4 Hz, 1H), 6.34-6.30(m, 1H), 3.67 631 N4- (3-Chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-1H NMR (DMSO-d6): d 10.78 (s, 1H), 9.23 (s, 1H), 9.03 (s, 1H),8.05 + + + fluoro-N2- (indol-6-yl)-2,4-pyrimidinediamine (d, J = 3.6 Hz,1H), 7.85 (d, J = 2.7 Hz, 1H), 7.79-7.73 (m, 2H), 7.36 (d, J = 8.4 Hz,1H), 7.19 (dd, J = 2.1 and 8.7 Hz, 1H), 7.16 (t, J = 3.0 Hz, 1H), 6.95(d, J = 9.0 Hz, 1H), 6.32-6.28 (m, 632 N4-[3-Chloro-4-(2-hydroxyethyleneoxy)phenyl]-5-fluoro-N2- 1H NMR (DMSO-d6): d 10.79 (s,1H), 9.19 (d, J = 1.2 Hz, 1H), 9.01 (s, + + −(indol-6-yl)-2,4-pyrimidinediamine 1H), 8.04 (d, J = 3.6 Hz, 1 H), 7.84(d, J = 2.7, 1 H), 7.79-7.73 (m, 2 H), 7.36 (d, J = 8.4 Hz, 1H), 7.19(dd, J = 1.8 and 8.4 Hz, 1H), 7.16 (t, J = 2.4 Hz, 1H), 7.05 (d, J = 9.3Hz, 1H), 633 5-Fluoro-N2-[3- (oxazol-2-yl)phenyl]-N4-[3,4- 1H NMR(DMSO-d6): d 9.76 (s, 1H), 9.63 (s, 1H), 8.33-8.29 (m, 1H), + −(tetrafluoroethylenedioxy)phenyl]-2,4-pyrimidinediamine 8.22 (d, J = 3.6Hz, 1H), 8.16-8.13 (m, 1H), 7.78-7.74 (m, 1H), 7.62 (dd, J = 2.4 and 9.0Hz, 1H), 7.58-7.53 (m, 1H), 7.42-7.31 (m, 3H), ; LCMS: purity: 92%; MS(m/e): 478 (MH+). 634 5-Fluoro-N4-methyl-N2-[3-(oxazol-2-yl)phenyl]-N4-[3,4- 1H NMR (DMSO-d6): d 9.67 (s, 1H), 8.57 (t,J = 1.8 Hz, 1H), 8.18-8.16 − + −(tetrafluoroethylenedioxy)phenyl]-2,4-pyrimidinediamine (m, 1H), 8.09(d, J = 5.7 Hz, 1H), 7.72-7.66 (m, 1H), 7.60 (d, J = 1.8 Hz, 1H),7.54-7.47 (m, 2H), 7.39-7.32 (m, 3H), 3.53 (s, 3H); LCMS: purity: 96%;MS (m/e): 492 (MH+). 635 N2-[3,5-Dimethyl-4- (N- 1H NMR (DMSO-d6): d9.02 (s, 1H), 8.12-8.06 (m, 1H), 7.88 (d, J = + + +methylamino)carbonylmethyleneoxyphenyl]-N4- (3,4- 5.7 Hz, 1H), 7.34 (s,2H), 6.83 (d, J = 6.9 Hz, 1H), 6.82 (s, 1H), 6.73ethylenedioxyphenyl)-5-fluoro-N4-methyl-2,4- (dd, J = 3.0 and 9.0 Hz,1H), 4.24 (s, 4H), 4.11 (s, 2H), 3.38 (s, 3H), pyrimidinediamine 2.69(d, J = 4.8 Hz, 3H), 2.16 (s, 6H); LCMS: pu 636 N2-[3,5-Dimethyl-4- (N-1H NMR (DMSO-d6): d 9.15 (s, 1H), 8.12-8.05 (m, 1H), 8.02 (d, J = + + +methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4- 5.7 Hz, 1H), 8.02(d, J = 5.7 Hz, 1H), 7.55 (dd, J = 0.9 and 2.7 Hz, 1H), methyl-N4-[3,4-(tetrafluoroethylenedioxy)phenyl]-2,4- 7.48 (d, J = 9.3 Hz, 1H), 7.31(s, 2H), 7.27 (dd, J = 0.9 and 2.1 Hz, 1H), pyrimidinediamine 4.11 (s,2H), 3.46 (s, 3H), 2.69 (d, J = 4.8 637 N2-[3,5-Dimethyl-4- (N- 1H NMR(DMSO-d6): d 9.59 (s, 1H), 9.14 (s, 1H), 8.16-8.08 (m, 3H), + −methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4-[3,4- 7.61 (dd, J =2.7 and 9.0 Hz, 1H), 7.40 (d, J = 9.0 Hz, 1H), 7.25 (s, 2H),(tetrafluoroethylenedioxy)phenyl]-2,4-pyrimidinediamine 4.12 (s, 2H),2.69 (d, J = 4.8 Hz, 3H), 2.15 (s, 6H); LCMS: purity: 99%; MS (m/e): 526(MH+). 638 N2-[3,5-Dimethyl-4- (N- 1H NMR (DMSO-d6): d 9.07 (s, 1H),8.13-8.05 (m, 1H), 7.94 (d, J = + + +methylamino)carbonylmethyleneoxyphenyl]-N4- (3,5- 5.7 Hz, 1H), 7.35 (s,2H), 6.44 (dd, J = 0.6 and 2.4 Hz, 2H), 6.39 (t, J =dimethoxyphenyl)-5-fluoro-N4-methyl-2,4-pyrimidinediamine 2.4 Hz, 1H),4.16 (s, 2H), 3.72 (s, 6H), 3.43 (s, 3H), 2.69 (d, J = 4.8 Hz, 3H), 2.16(s, 6H); LCMS: purity: 99%; MS 639 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 10.60 (s, 1H), 9.45 (s, 1H), 9.09 (s, 1H), 8.04 + + − [1-(methoxycarbonylmethylene)indol-6-yl]-2,4- (d, J = 3.6 Hz, 1H), 7.57 (s,1H), 7.40-7.33 (m, 2H), 7.31-7.24 (m, 2H), pyrimidinediamine 7.20 (d, J= 3.3 Hz, 1H), 6.81 (d, J = 8.7 Hz, 1H), 3.35 (d, J = 2.4 Hz, 1H), 4.91(s, 2H), 3.63 (s, 3H), 1.40 (s, 6H 640 N4-[3-Chloro-4- (N- 1H NMR(DMSO-d6): d 9.42 (s, 1H), 9.24 (s, 1H), 8.07 (d, J = 3.9 Hz, + + −methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N2-[1- 1H), 7.92-7.84(m, 2H), 7.71 (dd, J = 2.7 and 9.3 Hz, 1H), 7.55 (s, 1H),(methoxycarbonylmethylene)indol-6-yl]-2,4-pyrimidinediamine 7.41 (d, J =8.4 Hz, 1H), 7.29 (dd, J = 1.5 and 8.4 Hz, 1H), 7.20 (d, J = 3.3 Hz,1H), 6.94 (d, J = 9.0 Hz, 1H), 6.36 641 N4-(4-Chloro-3-methoxyphenyl)-5-fluoro-N2-[1- 1H NMR (DMSO-d6): d 9.34 (s,1H), 9.10 (s, 1H), 8.09 (d, J = 3.6 Hz, + + +(methoxycarbonylmethylene)indol-6-yl]-2,4-pyrimidinediamine 1H),7.62-7.59 (m, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.49 (dd, J = 2.4 and 8.4Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.27-7.22 (m, 2H), 7.20 (d, J = 3.3Hz, 1H), 6.36 (dd, J = 0.6 and 3.0 Hz, 1H), 642 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1- 1H NMR (DMSO-d6): d 9.19 (s,1H), 9.14 (s, 1H), 8.02 (d, J = 3.9 Hz, + + −(methoxycarbonylmethylene)indol-6-yl]-2,4-pyrimidinediamine 1H), 7.63(s, 1H), 7.40-7.31 (m, 2H), 7.30-7.17 (m, 3H), 6.74 (d, J = 9.0 Hz, 1H),6.35 (d, J = 2.7 Hz, 1H), 4.90 (s, 2H), 4.21 (s, 4H), 3.63 (s, 3H);LCMS: purity: 93%; MS (m/e): 450 (MH+) 643 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 10.56 (s, 1H), 9.20 (s, 1H), 8.79 (s, 1H), 8.00 + + − [1-(methoxycarbonylmethylene)indol-5-yl]-2,4- (d, J = 3.6 Hz, 1H), 7.86 (s,1H), 7.33 (dd, J = 2.1 and 8.7 Hz, 1H), 7.27- pyrimidinediamine 7.16 (m,4H), 6.83 (d, J = 8.7 Hz, 1H), 6.27 (d, J = 3.0 Hz, 1H), 5.05 (s, 2H),3.66 (s, 3H), 1.40 (s, 6H); LCMS: p 644 N4-[3-Chloro-4- (N- 1H NMR(DMSO-d6): d 9.22 (s, 1H), 8.96 (s, 1H), 8.03 (d, J = 3.9 Hz, + + −methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N2-[1- 1H), 7.90-7.72(m, 4H), 7.28-7.23 (m, 3H), 6.94 (d, J = 8.7 Hz, 1H),(methoxycarbonylmethylene)indol-5-yl]-2,4-pyrimidinediamine 6.32 (d, J =3.0 Hz, 1H), 5.07 (s, 2H), 4.53 (s, 2H), 3.67 (s, 3H), 2.67 (d, J = 4.5Hz, 3H), ; LCMS: purity: 90%; MS (m 645 N4-(4-Chloro-3-methoxyphenyl)-5-fluoro-N2-[1- 1H NMR (DMSO-d6): d 9.32 (s,1H), 8.96 (s, 1H), 8.07 (d, J = 3.6 Hz, + + −(methoxycarbonylmethylene)indol-5-yl]-2,4-pyrimidinediamine 1H), 7.84(s, 1H), 7.55-7.47 (m, 2H), 7.28-7.17 (m, 4H), 6.29 (d, J = 3.0 Hz, 1H),5.08 (s, 2H), 3.67 (s, 3H), 3.64 (s, 3H); LCMS: purity: 96%; MS (m/e):457 (MH+). 646 N4- (3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1- 1H NMR(DMSO-d6): d 9.18 (s, 1H), 8.94 (s, 1H), 8.02 (d, J = 3.0 Hz, + + −(methoxycarbonylmethylene)indol-5-yl]-2,4-pyrimidinediamine 1H),7.82-7.76 (m, 2H), 7.70 (dd, J = 2.1 and 9.0 Hz, 1H), 7.27-7.21 (m, 3H),7.03 (d, J = 9.0 Hz, 1H), 6.30 (d, J = 2.7 Hz, 1H), 5.06 (s, 2H), 3.83(s, 3H), 3.66 (s, 3H); LCMS: purity: 98% 647 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1- 1H NMR (DMSO-d6): d 10.18 (s,1H), 9.99 (s, 1H), 8.16 (d, J- 4.5 Hz, + + −(methoxycarbonylmethylene)indol-5-yl]-2,4-pyrimidinediamine 1H), 7.74(s, 1H), 7.46-7.18 (m, 3H), 7.34-7.18 (m, 3H), 6.83 (d, J = 8.1 Hz, 1H),6.46 (d, J = 3.0 Hz, 1H), 5.20 (s, 2H), 4.29 (s, 4H), 3.74 (s, 3H);LCMS: purity: 92%; MS (m/e): 450 (MH+ 648 N4-[3-Chloro-4- (N- 1H NMR(DMSO-d6): d 9.25 (s, 1H), 9.07 (s, 1H), 8.04 (d, J = 3.6 Hz, + + − +methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N2-[1- (N- 1H),7.90-7.83 (m, 3H), 7.77-7.73 (m, 1H), 7.55-7.52 (m, 1H), 7.39 (d,methylamino)carbonylmethyleneindol-6-yl]-2,4- J = 9.0 Hz, 1H), 7.32-7.26(m, 1H), 7.16 (d, J = 3.3 Hz, 1H), 6.91 (d, J = pyrimidinediamine 9.3Hz, 1H), 6.33 (d, J = 3.0 Hz, 1H), 4.62 ( 649 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1- (N- 1H NMR (DMSO-d6): d 9.06(s, 1H), 9.02 (s, 1H), 7.99 (d, J = 3.9 Hz, + + −methylamino)carbonylmethyleneindol-6-yl]-2,4- 1H), 7.88-7.82 (m, 1H),7.58 (s, 1H), 7.39-7.33 (m, 2H), 7.32-7.25 (m, pyrimidinediamine 2H),7.16 (d, J = 3.3 Hz, 1H), 6.71 (d, J = 8.7 Hz, 1H), 6.33 (d, J = 3.3 Hz,1H), 4.63 (s, 2H), 4.19 (s, 4H), 2.58 (d 650 5-Fluoro-N4-[2-(2-hydroxyethyleneoxy)pyrid-5-yl]-N2-[1- (N- 1H NMR (DMSO-d6): d 9.26(s, 1H), 8.98 (s, 1H), 8.51 (s, 1H), 8.07 +methylamino)carbonylmethyleneindol-5-yl]-2,4- (dd, J = 2.4 and 9.0 Hz,1H), 8.03 (d, J = 3.9 Hz, 1H), 7.98-7.92 (m, pyrimidinediamine 1H), 7.87(s, 1H), 7.24-7.14 (m, 3H), 6.76 (d, J = 9.0 Hz, 1H), 6.27 (d, J = 3.0Hz, 1H), 4.84 (t, J = 5.4 Hz, 1H), 4.72 ( 651 N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[1- (N- 1H NMR(DMSO-d6): d 9.55 (s, 1H), 9.09 (s, 1H), 8.15-7.99 (m, 2H), +methylamino)carbonylmethyleneindol-5-yl]-2,4- 8.02-7.95 (m, 1H), 7.89(dd, J = 1.5 and 9.6 Hz, 1H), 7.75 (s, 1H), 7.40 pyrimidinediamine (d, J= 9.0 Hz, 1H), 7.27-7.21 (m, 3H), 6.30 (d, J = 2.7 Hz, 1H), 4.73 (s,2H), 2.61 (d, J = 4.5 Hz, 3H); LCMS: purity 652 N4-[3-Chloro-4- (N- 1HNMR (DMSO-d6): d 9.88 (s, 1H), 9.70 (s, 1H), 8.12-8.03 (m, 2H), + +methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N2-[1- (N- 7.94-7.87(m, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.69-7.63 (m, 2H), 7.35-methylamino)carbonylmethyleneindol-5-yl]-2,4- 7.27 (m, 2H), 7.17 (d, J =8.7 Hz, 1H), 6.94 (d, J = 9.0 Hz, 1H), 6.35 (d, pyrimidinediamine J =3.0 Hz, 1H), 4.77 (s, 2H), 4.55 (s, 2H), 2. 653 N4-(4-Chloro-3-methoxyphenyl)-5-fluoro-N2-[1- (N- 1H NMR (DMSO-d6): d 10.22(s, 1H), 9.91 (s, 1H), 8.16 (d, J = 4.8 Hz, +methylamino)carbonylmethyleneindol-5-yl]-2,4- 1H), 8.12-8.05 (m, 1H),7.70-7.66 (m, 1H), 7.52-7.48 (m, 1H), 7.42 (d, pyrimidinediamine J = 7.8Hz, 1H), 7.37-7.28 (m, 3H), 7.16-7.10 (m, 1H), 6.35 (d, J = 2.7 Hz, 1H),4.79 (s, 2H), 3.63 (s, 3H), 2.62 (d, 654 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1- (N- 1H NMR (DMSO-d6): d 10.21(s, 1H), 9.94 (s, 1H), 8.16-8.03 (m, 2H), +methylamino)carbonylmethyleneindol-5-yl]-2,4- 7.79-7.74 (m, 1H),7.65-7.58 (m, 2H), 7.37-7.30 (m, 2H), 7.14 (d, J = pyrimidinediamine 8.4Hz, 1H), 7.05 (d, J = 8.7 Hz, 1H), 6.37 (d, J = 3.0 Hz, 1H), 4.78 (s,2H), 3.84 (s, 3H), 2.61 (d, J = 4.5 Hz, 3H); LC 655 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1- (N- 1H NMR (DMSO-d6): d 10.19(bs, 1H), 10.04 (bs, 1H), 8.12-8.03 (m, +methylamino)carbonylmethyleneindol-5-yl]-2,4- 2H), 7.66-7.61 (m, 1H),7.36-7.30 (m, 2H), 7.27-7.09 (m, 3H), 6.78 (d, pyrimidinediamine J = 8.4Hz, 1H), 6.38 (d, J = 2.7 Hz, 1H), 4.79 (s, 2H), 4.23 (s, 4H), 2.61 (d,J = 4.2 Hz, 3H); LCMS: purity: 99%; MS ( 656 N4-[3-Chloro-4-(N-methylamino)carbonylphenyl]-5-fluoro-N2- 1H NMR (DMSO-d6): d 9.46 (s,1H), 9.07 (s, 1H), 8.24-8.17 (m, 1H), + [1-(N-methylamino)carbonylmethyleneindol-5-yl]-2,4- 8.11 (d, J = 3.0 Hz,1H), 8.00-7.94 (m, 1H), 7.94-7.86 (m, 2H), 7.77 (s, pyrimidinediamine1H), 7.31-7.22 (m, 4H), 6.33 (d, J = 3.3 Hz, 1H), 4.73 (s, 2H), 2.73 (d,J = 4.8 Hz, 3H), 2.60 (d, J = 4.8 Hz, 3H); LC 657 2-Chloro-5-fluoro-N4-(2-methoxypyrid-5-yl)-N4-methyl-4- 1H NMR (DMSO-d6): d 8.21 (d, J = 3.0Hz, 1H), 8.15 (d, J = 5.7 Hz, − − pyrimidineamine 1H), 7.78 (dd, J = 2.7and 8.7 Hz, 1H), 6.87 (d, J = 8.7 Hz, 1H), 3.86 (s, 3H), 3.38 (s, 3H);LCMS: purity: 95%; MS (m/e): 269 (MH+). 658 2-Chloro-N4-(4-chloro-3-trifluoromethylphenyl)-5-fluoro-N4- 1H NMR (DMSO-d6): d 8.25(d, J = 5.4 Hz, 1H), 7.97-7.94 (m, 1H), − − methyl-4-pyrimidineamine7.78-7.72 (m, 2H), 3.45 (s, 3H); LCMS: purity: 96%; MS (m/e): 341 (MH+).659 2-Chloro-N4- (4-chloro-3-methoxyphenyl)-5-fluoro-N4-methyl- 1H NMR(DMSO-d6): d 8.18 (d, J = 5.1 Hz, 1H), 7.42 (d, J = 8.7 Hz, − −4-pyrimidineamine 1H), 7.24 (s, 1H), 6.96 (d, J = 8.7 Hz, 1H), 3.82 (s,1H), 3.31 (s, 3H); LCMS: purity: 99%; MS (m/e): 303 (MH+). 6602-Chloro-N4- (3-chloro-4-methoxyphenyl)-5-fluoro-N4-methyl- 1H NMR(DMSO-d6): d 8.14 (d, J = 5.4 Hz, 1H), 7.56 (d, J = 2.7 Hz, − −4-pyrimidineamine 1H), 7.34 (dd, J = 2.4 and 8.7 Hz, 1H), 7.15 (d, J =8.4 Hz, 1H), 3.87 (s, 3H), 3.36 (s, 3H); LCMS: purity: 96%; MS (m/e):303 (MH+). 661 2-Chloro-N4-[3-chloro-4- (N- 1H NMR (DMSO-d6): d 8.15 (d,J = 5.4 Hz, 1H), 7.94-7.87 (m, 1H), − −methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4- 7.58 (d, J = 2.4Hz, 1H), 7.32 (dd, J = 2.4 and 8.7 Hz, 1H), 7.02 (d, J =methyl-4-pyrimidineamine 9.0 Hz, 1H), 4.60 (s, 2H), 3.36 (s, 3H), 2.66(d, J = 4.8 Hz, 3H), ; LCMS: purity: 90%; MS (m/e): 360 (MH+). 662 N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[1- (N- 1H NMR(DMSO-d6): d 10.22 (s, 1H), 9.88 (s, 1H), 8.22 (d, J = 3.9 Hz, + + −methylamino)carbonylmethyleneindol-6-yl]-2,4- 1H), 8.14 (d, J = 2.7 Hz,1H), 8.02-7.95 (m, 1H), 7.84-7.78 (m, 1H), pyrimidinediamine 7.49 (d, J= 8.1 Hz, 1H), 7.45-7.37 (m, 2H), 7.27 (d, J = 2.7 Hz, 1H), 7.27 (d, J =2.7 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H) 663 N4-(4-Chloro-3-methoxyphenyl)-5-fluoro-N2-[1- (N- 1H NMR (DMSO-d6): d 10.13(s, 1H), 9.90 (s, 1H), 8.10 (d, J = 4.5 Hz, + −methylamino)carbonylmethyleneindol-6-yl]-2,4- 1H), 7.91 (d, J = 3.9 Hz,1H), 7.49-7.34 (m, 4H), 7.23 (d, J = 3.3 Hz, pyrimidinediamine 1H), 7.17(d, J = 8.4 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.37 (d, J = 3.0 Hz, 1H),4.62 (s, 2H), 3.52 (s, 3H), 2.51 (d, 664 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1- (N- 1H NMR (DMSO-d6): d 10.21(s, 1H), 10.04 (s, 1H), 8.14 (d, J = 5.1 + + −methylamino)carbonylmethyleneindol-6-yl]-2,4- Hz, 1H), 7.98-7.92 (m,1H), 7.84 (d, J = 2.7 Hz, 1H), 7.60 (dd, J = 2.4 pyrimidinediamine and8.7 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.39 (s, 1H), 7.30 (d, J = 3.3Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.01 (d, J = 665 N4-[3-Chloro-4-(N-methylamino)carbonylphenyl]-5-fluoro-N2- 1H NMR (DMSO-d6): d 9.50 (s,1H), 9.19 (s, 1H), 8.28-8.20 (m, 1H), + − [1-(N-methylamino)carbonylmethyleneindol-6-yl]-2,4- 8.12 (d, J = 3.3 Hz,1H), 7.97-7.84 (m, 3H), 7.53 (s, 1H), 7.42 (d, J = 8.7 pyrimidinediamineHz, 1H), 7.32-7.25 (d, J = 3.3 Hz, 1H), 6.35 (d, J = 3.0 Hz, 1H), 4.63(s, 2H), 2.74 (d, J = 4.5 Hz, 3H), 2.58 (d, J 666 2-Chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4- 1H NMR (DMSO-d6): d 9.94 (s, 1H),8.28 (dd, J = 0.6 and 3.6 Hz, 1H), − − pyrimidineamine 7.75 (d, J = 2.1Hz, 1H), 7.58 (dd, J = 2.4 and 8.7 Hz, 1H), 7.16 (d, J = 8.7 Hz, 1H),3.84 (s, 3H); LCMS: purity: 96%; MS (m/e): 288 (M+). 667 5-Fluoro-N2-[3-(oxazol-2-yl)phenyl]-N4- (3,4,5- 1H NMR (DMSO-d6): d 9.38 (s, 1H), 9.28(s, 1H), 8.28 (s, 1H), 8.14- + trimethoxyphenyl)-2,4-pyrimidinediamine8.10 (m, 2H), 7.87 (d, J = 7.2 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.34-7.27 (m, 2H), 7.06 (s, 2H), 3.70 (s, 6H), 3.63 (s, 3H); LCMS: purity:98%; MS (m/e): 438 (MH+). 668 N4- (3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2,3,4- 1H NMR (DMSO-d6): d 9.10 (s, 1H), 7.96 (d, J = 3.9 Hz, 1H), 7.75(s, + trimethoxyphenyl)-2,4-pyrimidinediamine 1H), 7.50 (d, J = 8.7 Hz,1H), 7.26 (d, J = 2.4 Hz, 1H), 7.10 (dd, J = 2.4 Hz, 1H), 6.74-6.64 (m,2H), 4.25-4.18 (m, 4H), 3.77 (s, 3H), 3.75 (s, 3H), 3.74 (s, 3H); LCMS:purity: 99%; MS (m/ 669 N4- (3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(2,3,4- 1H NMR (DMSO-d6): d 9.26 (s, 1H), 8.01 (d, J = 3.6 Hz, 1H), 7.86(s, − trimethoxyphenyl)-2,4-pyrimidinediamine 1H), 7.81 (d, J = 2.7 Hz,1H), 7.54 (dd, J = 2.4 and 9.0 Hz, 1H), 7.43 (d, J = 9.0 Hz, 1H), 7.03(d, J = 9.0 Hz, 1H), 6.70 (d, J = 9.3 Hz, 1H), 3.81 (s, 3H), 3.76 (s,3H), 3.74 (s, 3H), 3.73 670 N4- (4-Chloro-3-methoxyphenyl)-5-fluoro-N2-(2,3,4- 1H NMR (DMSO-d6): d 816 (d, J = 4.8 Hz, 1H), 7.56-7.51 (m, 1H),− trimethoxyphenyl)-2,4-pyrimidinediamine 7.36-7.24 (m, 4H), 6.74 (d, J= 9.3 Hz, 1H), 3.80 (s, 3H), 3.74 (s, 3H), 3.73 (s, 3H), 3.68 (s, 3H), ;LCMS: purity: 95%; MS (m/e): 436 (MH+). 671 N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2- (2,3,4- 1H NMR(DMSO-d6): d 8.20 (d, J = 4.5 Hz, 1H), 8.05 (d, J = 2.7 Hz, +trimethoxyphenyl)-2,4-pyrimidinediamine 1H), 7.73-7.66 (m, 1H), 7.45 (d,J = 9.6 Hz, 1H), 7.24 (d, J = 8.7 Hz, 1H), 6.75 (d, J = 9.0 Hz, 1H),3.78 (s, 3H), 3.74 (s, 3H), 3.73 (s, 3H); LCMS: purity: 95%; MS (m/e):490 (MH+). 672 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 10.73 (s, 1H), 10.44 (s, 1H), 8.21 (d, J = 4.8 +(2,3,4-trimethoxyphenyl)-2,4-pyrimidinediamine Hz, 1H), 7.43-7.32 (m,1H), 7.27-7.13 (m, 2H), 6.89 (d, J = 8.4 Hz, 1H), 6.65 (d, J = 9.6 Hz,1H), 3.77 (s, 3H), 3.76 (s, 3H), 3.74 (s, 3H), 1.41 (s, 6H); LCMS:purity: 98%; MS (m/e): 470 (MH 673 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 11.14 (s, 1H), 9.98 (s, 1H), 9.63 (s, 1H), 8.17 + + N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine (d, J = 3.9 Hz, 1H),7.62-7.52 (m, 3H), 7.36-7.25 (m, 4H), 6.87 (s, 2H), Benzenesulfonic AcidSalt 3.66 (s, 6H), 3.61 (s, 3H), 1.43 (s, 6H). 674 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 11.13 (s, 1H), 9.95 (s, 1H), 9.62 (s, 1H), 8.18 + + N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine (d, J = 3.9 Hz, 1H), 7.56(d, J = 9.0 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), Methanesulfonic Acid Salt6.88 (s, 2H), 3.66 (s, 6H), 3.61 (s, 3H), 2.33 (s, 3H), 1.43 (s, 6H).675 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 11.12 (s, 1H), 9.89 (s, 1H), 9.57 (s, 1H), 8.17 + + N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine p-Toluene (d, J = 3.9 Hz,1H), 7.57 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 7.8 Hz, 2H), Sulfonic AcidSalt 7.31 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 7.8 Hz, 2H), 6.89 (s, 2H),3.66 (s, 6H), 3.61 (s, 3H), 2.28 (s, 3H), 1.43 (s, 6 676 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 11.12 (s, 1H), 9.81 (s, 1H), 9.53 (s, 1H), 8.16 + + N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 4- (d, J = 4.2 Hz, 1H),7.58 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H),Hydroxybenzenesulfonic Acid Salt 7.31 (d, J = 8.7 Hz, 1H), 6.90 (s, 2H),6.64 (d, J = 8.7 Hz, 2H), 3.66 (s, 6H), 3.61 (s, 3H), 1.43 (s, 6H). 677N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 11.10 (s, 1H), 9.72 (s, 1H), 9.47 (s, 1H), 8.15 + N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 2,4,6- (d, J = 4.2 Hz,1H), 7.62-7.56 (m, 1H), 7.31 (d, J = 8.1 Hz, 1H), 6.91 (s,Trimethylbenzenesulfonic Acid Salt 2H), 6.72 (s, 2H), 3.66 (s, 6H), 3.61(s, 3H), 2.48 (s, 6H), 2.16 (s, 3H), 1.43 (s, 6H). 678 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 11.08 (s, 2H), 9.46 (s, 2H), 9.30 (s, 2H), 8.91 + + N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 0.5 (s, 1H), 8.70 (d, J =5.4 Hz, 1H), 8.37 (dd, J = 1.5 and 7.8 Hz, 1H), 8.13 Pyridine-3-sulfonicAcid Salt (d, J = 3.6 Hz, 2H), 7.80-7.74 (m, 1H), 7.62 (d, J = 8.1 Hz,2H), 7.31 (d, J = 8.1 Hz, 2H), 6.97 (s, 4H), 3.66 (s, 1 679 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 11.08 (s, 1H), 9.44 (s, 1H), 9.26 (s, 1H), 8.13 + + N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine p- (d, J = 3.3 Hz, 1H),7.63 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.1 Hz, 2H), EthylbenzenesulfonicAcid Salt 7.31 (d, J = 8.1 Hz, 1H), 7.12 (d, J = 7.8 Hz, 2H), 6.97 (s,2H), 3.65 (s, 6H), 3.59 (s, 3H), 2.57 (q, J = 7.8 Hz, 2H), 680 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 11.08 (s, 2H), 9.54 (s, 2H), 9.35 (s, 2H), 8.14 + + N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 0.5 1,2- (d, J = 3.9 Hz,2H), 7.60 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H),Ethanedisulfonic Acid Salt 6.95 (s, 4H), 3.66 (s, 12H), 3.60 (s, 6H),2.62 (s, 4H), 1.43 (s, 12H). 681 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 11.11 (s, 1H), 9.83 (s, 1H), 9.54 (s, 1H), 8.17 + + N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine (1R)-10- (d, J = 3.9 Hz,1H), 7.57 (d, J = 8.7 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), CamphorsulfonicAcid Salt 6.99 (s, 2H), 3.66 (s, 6H), 3.61 (s, 3H), 2.86 (d, J = 14.7Hz, 1H), 2.67 (t, J = 9.9 Hz, 1H), 2.38 (d, J = 14.7 Hz, 1H) 682 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 11.08 (s, 1H), 9.55 (s, 1H), 9.36 (s, 1H), 8.14 + + N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine (1S)-10- (d, J = 3.9 Hz,1H), 7.60 (d, J = 8.7 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), CamphorsulfonicAcid Salt 6.94 (s, 2H), 3.66 (s, 6H), 3.60 (s, 3H), 2.85 (d, J = 14.7Hz, 1H), 2.68 (t, 11.4 Hz, 1H), 2.36 (d, J = 14.7 Hz, 1H), 683 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 11.04 (s, 1H), 9.08-8.90 (m, 2H), 8.07 (d, J = + + N2-[1-(N-methylamino)carbonylmethyleneindol-5-yl]-2,4- 3.3 Hz, 1H), 7.99-7.89(m, 1H), 7.81-7.96 (m, 1H), 7.70-7.64 (m, 1H), pyrimidinediamine7.29-7.20 (m, 4H), 6.29 (d, J = 3.0 Hz, 1H), 4.73 (s, 2H), 2.61 (d, J =4.5 Hz, 3H), 1.42 (s, 6H), ; LCMS: purity: 99%; 684 N2-(4-Chloro-3,5-dimethylphenyl)-N4- (2,2-dimethyl-3-oxo-4H- 1H NMR(DMSO-d6): d 11.13 (s, 1H), 9.68 (s, 1H), 9.46 (s, 1H), 8.17 +5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine p- (d, J = 3.6Hz, 1H), 7.51-7.35 (m, 6H), 7.09 (d, J = 8.4 Hz, 2H), 2.28 (s,Toluenesulfonic Acid Salt 3H), 2.22 (s, 6H), 1.43 (s, 6H). 685 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 11.31 (s, 1H), 9.89 (s, 1H), 9.66 (s, 1H), 8.18 + + N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine Hydrogen (d, J = 4.5 Hz,1H), 7.55 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), Chloride Salt6.89 (s, 2H), 3.65 (s, 6H), 3.61 (s, 3H), 1.43 (s, 6H) 686 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2- (3,5- 1H NMR(DMSO-d6): d 11.07 (s, 1H), 9.32 (s, 1H), 9.27 (s, 1H), 8.13 + +dichloro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine (d, J = 3.3 Hz,1H), 7.63 (s, 2H), 7.45 (d, J = 8.7 Hz, 1H), 7.35 (d, J = 8.7 Hz, 1H),1.43 (s, 6H); LCMS: purity: 92%; MS (m/e): 467 (MH⁺). 687 N2,N4-Bis(3-oxo-2,2,4-trimethyl-5-pyrid[1,4]oxazin-6-yl)-5- 1H NMR (DMSO-d6): d9.49 (bs, 2H), 8.18 (d, J = 3.3 Hz, 1H), 7.93 (d, +fluoro-2,4-pyrimidinediamine J = 8.7 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H),7.37 (d, J = 8.7 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 3.34 (s, 3H), 3.33(s, 3H), 1.44 (s, 6H), 1.41 (s, 6H); LCMS: purity: 98%; MS (m/e): 509(MH⁺). 688 N2,N4-Bis (2,2-dimethyl-4-carbomethoxymethyl-3-oxo-5- 1H NMR(DMSO-d6): d 9.55 (s, 1H), 9.49 (s, 1H), 8.19 (d, J = 2.7 Hz, −pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 1H), 7.97 (d, J = 8.7 Hz,1H), 7.79 (d, J = 8.7 Hz, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.38 (d, J =8.7 Hz, 1H), 4.81 (s, 2H), 4.80 (s, 2H), 3.67 (s, 3H), 3.66 (s, 3H),1.48 (s, 6H), 1.45 (s, 6H 689 5-Fluoro-N4-(3-oxo-2,2,4-trimethyl-5-pyrid[1,4]oxazin-6-yl)-N2- 1H NMR (DMSO-d6): d9.42 (s, 1H), 9.13 (s, 1H), 8.14 (d, J = 3.6 Hz, +(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 1H), 7.80 (d, J = 8.4 Hz,1H), 7.32 (d, J = 8.4 Hz. 1H), 7.03 (s, 2H), 3.66 (s, 6H), 3.60 (s, 3H),1.44 (s, 6H); LCMS: purity: 97%; MS (m/e): 485 (MH⁺). 690 N4-(2,2-Dimethyl-4-carbomethoxymethyl-3-oxo-5- 1H NMR (DMSO-d6): d 9.46 (s,1H), 9.15 (s, 1H), 8.15 (d, J = 3.6 Hz, +pyrid[1,4]oxazin-6-yl)-5-fluoro-N2- (3,4,5-trimethoxyphenyl)-2,4- 1H),7.86 (d, J = 8.7 Hz, 1H), 7.37 (d, J = 8.7 Hz, 1H), 7.04 (s, 2H), 4.80pyrimidinediamine (s, 2H), 3.67 (s, 6H), 3.66 (s, 3H), 3.60 (s, 3H),1.47 (s, 6H); LCMS: purity: 96%; MS (m/e): 543 (MH⁺). 691 N4-(2,2-Dimethyl-4-carbomethoxymethyl-3-oxo-5- 1H NMR (DMSO-d6): d 9.27 (s,1H), 8.22 (d, J = 4.8 Hz, 1H), 7.42 (d, +pyrid[1,4]oxazin-6-yl)-5-fluoro-N4-carbomethoxymethyl-N2- J = 8.4 Hz,1H), 6.98 (s, 2H), 6.81 (dd, J = 3.3 and 8.4 Hz, 1H), 4.83 (s,(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 2H), 4.63 (s, 2H), 3.72(s, 6H), 3.63 (s, 3H), 3.59 (s, 3H), 3.57 (s, 3H), 1.47 (s, 6H); LCMS:purity: 99%; MS (m 692 N2-[3,5-Dimethoxy-4- (2-(N-morpholino)ethyloxo)phenyl]-N4- 1H NMR (DMSO-d6): d 11.04 (s, 1H),9.14 (s, 1H), 9.09 (s, 1H), 8.11 + +(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4- (d, J =3.6 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H),pyrimidinediamine 7..02 (s, 2H), 3.87 (t, J = 6.0 Hz, 2H), 3.65 (s, 6H),3.58-3.53 (m, 4H), 2.58 (t, J = 6.0 Hz, 2H), 2.47-2.42 (m, 4H), 693 N2,N4-Bis (2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5- 1H NMR(DMSO-d6): d 11.07 (s, 1H), 10.91 (s, 1H), 9.27 (s, 1H), +fluoro-2,4-pyrimidinediamine 9.12 (s, 1H), 8.13 (d, J = 3.3 Hz, 1H),7.69 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 9.0 Hz, 1H), 7.32 (d, J = 8.4 Hz,1H), 7.22 (d, J = 9.0 Hz, 1H), 1.43 (s, gH), 1.39 (s, 6H); LCMS: purity:99%; MS 694 N4- (3-Chloro-4-methoxyphenyl)-N2- (1-ethylindazol-5-yl)-5-1H NMR (DMSO-d6): d 10.36 (s, 1H), 10.21 (s, 1H), 8.24 (d, 1H, J = + + −fluoro-2,4-pyrimidinediamine 4.9 Hz), 7.92 (s, 1H), 7.83 (s, 1H), 7.74(d, 1H, J = 2.6 Hz), 7.65 (d, 1H, J = 9.1 Hz), 7.54 (app dd, 1H, J = 2.3and 9.1 Hz), 7.38 (dd, 1H, J = 1.8 and 9.1 Hz), 7.09 (d, 1H, J = 9.1Hz), 4.40 (qt, 2H, J = 7.0 Hz), 3.83 (s, 3H), 1.38 (t, 3H, J = 7.0 Hz).LCMS: ret. time: 9.30 min.; purity: 97%; MS (m/e): 414 (MH+) 695 N4-(3,4-Dichlorophenyl)-N2- (1-ethylindazol-5-yl)-5-fluoro-2,4- ¹H NMR(DMSO-d6): d 10.28 (s, 1H), 10.02 (s, 1H), 8.28 (d, 1H, J = − −pyrimidinediamine 4.7 Hz), 8.02 (d, 1H, J = 2.3 Hz), 7.94 (s, 1H), 7.87(s, 1H), 7.70 (s, 1H), 7.66 (d, 1H, J = 9.1 Hz), 7.52 (d, 1H, J = 8.8Hz), 7.42 (dd, 1H, J = 2.3 and 8.8 Hz), 4.41 (qt, 2H, J = 7.0 Hz 696 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2- (1- ¹H NMR (DMSO-d6): d10.77 (s, 1H), 10.39 (s, 1H), 10.21 (s, 1H), + + + +ethylindazol-5-yl)-5-fluoro-2,4-pyrimidinediamine 8.22 (d, 1H, J = 5.3Hz), 7.89 (s, 2H), 7.61 (d, 1H, J = 8.8 Hz), 7.37 (d, 1H, J = 8.8 Hz),7.20 (dd, 2H, J = 2.3 and 8.2 Hz), 6.81 (d, 1H, J = 8.2 Hz), 4.39 (qt,2H, J = 7.0 Hz), 1.37 (s, 6 697 N2- (1-Ethylindazol-5-yl)-5-fluoro-N4-(4-fluoro-3- ¹H NMR (DMSO-d6): d 10.42 (s, 1H), 10.29 (s, 1H), 8.26 (d,1H, J = + + − methoxyphenyl)-2,4-pyrimidinediamine 4.9 Hz), 7.89 (s,2H), 7.63 (d, 1H, J = 8.8 Hz), 7.44 (d, 1H, J = 8.2 Hz), 7.37 (d, 1H, J= 9.0 Hz), 7.31-7.23 (m, 1H), 7.19 (dd, 1H, J = 8.8 and 11.8 Hz), 4.41(qt, 2H, J = 7.0 Hz), 3.60 698 N4- (3-Chloro-4-methoxyphenyl)-N2-(1-ethylindazol-6-yl)-5- ¹H NMR (DMSO-d6): d 10.44 (s, 1H), 10.40 (s,1H), 8.32 (d, 1H, J = + + − fluoro-2,4-pyrimidinediamine 4.9 Hz), 7.92(s, 1H), 7.78 (app t, 2H, J = 2.6 Hz), 7.67 (d, 1H, J = 8.5 Hz),7.58-7.52 (dt, 1H, J = 2.6 and 9.1 Hz), 7.16 (d, 1H, J = 8.8 Hz), 7.10(d, 1H, J = 9.1 Hz), 4.11 (qt, 2H, J 699 N4- (3,4-Dichlorophenyl)-N2-(1-ethylindazol-6-yl)-5-fluoro-2,4- ¹H NMR (DMSO-d6): d 9.92 (s, 1H),9.78 (s, 1H), 8.27 (d, 1H, J = 4.1 + + pyrimidinediamine Hz 0, 8.08 (appd, 1H, J = 2.6 Hz), 7.93 (s, 1H), 7.91 (s, 1H), 7.76 (dt, 1H, J = 2.6and 8.1 Hz), 7.62 (d, 1H, J = 8.5 Hz), 7.54 (d, 1H, J = 8.8 Hz), 7.23(d, 1H, J = 8.5 Hz), 4.14 (qt, 2 700 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2- (1- ¹H NMR (DMSO-d6): d10.75 (s, 1H), 10.18 (s, 2H), 8.25 (d, 1H, J = + + +ethylindazol-6-yl)-5-fluoro-2,4-pyrimidinediamine 4.7 Hz), 7.94 (s, 1H),7.84 (s, 1H), 7.63 (d, 1H, J = 8.5 Hz), 7.27-7.17 (m, 3H), 6.86 (d, 1H,J = 8.5 Hz), 4.14 (qt, 2H, J = 7.0 Hz), 1.38 (s, 6H), 1.28 (t, 3H, J =7.0 Hz). LCMS: ret. t 701 N2- (1-Ethylindazol-6-yl)-5-fluoro-N4-(4-fluoro-3- ¹H NMR (DMSO-d6): d 10.18 (s, 2H), 8,26 (d, 1H, J = 4.7Hz), 7.93 (s, + + methoxyphenyl)-2,4-pyrimidinediamine 1H), 7.90 (s,1H), 7.62 (d, 1H, J = 8.5 Hz), 7.50-7.46 (m, 1H), 7.30- 7.27 (m, 1H),7.19-7.13 (m, 2H), 4.09 (qt, 2H, J = 7.0 Hz), 3.60 (s, 3H), 1.27 (t, 3H,J = 7.0 Hz). LCMS: ret. time 702 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2- (1-n- ¹H NMR (DMSO-d6): d 10.39(s, 1H), 10.26 (s, 1H), 8.26 (d, 1H, J = +propylindazol-5-yl)-2,4-pyrimidinediamine 4.7 Hz), 7.92 (s, 1H), 7.82(s, 1H), 7.75 (d, 1H, J = 2.7 Hz), 6.66 (d, 1H, J = 9.1 Hz), 7.54 (dt,1H, J = 2.3 and 9.1 Hz), 7.08 (d, 1H, J = 9.1 Hz), 4.33 (t, 2H, J = 7.0Hz), 3.83 (s, 3H) 703 N4- (3,4-Dichlorophenyl)-5-fluoro-N2-(1-n-propylindazol-5-yl)- ¹H NMR (DMSO-d6): d 10.21 (s, 1H), 9.93 (s,1H), 8.26 (d, 1H, J = 4.4 + 2,4-pyrimidinediamine Hz), 8.01 (d, 1H, J =2.6 Hz), 7.94 (s, 1H), 7.87 (s, 1H), 7.69 (dd, 1H, J = 1.8 and 8.8 Hz),7.65 (d, 1H, J = 9.1 Hz), 7.49 (d, 1H, J = 8.8 Hz), 7.41 (dd, 1H, J =9.1 Hz), 4.34 (t, 2H, 704 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- ¹H NMR(DMSO-d6): d 10.75 (s, 1H), 10.21 (s, 2H), 8.26 (d, 1H, J = + +(1-n-propylindazol-5-yl)-2,4-pyrimidinediamine 4.9 Hz), 7.94 (s, 1H),7.83 (s, 1H), 7.63 (d, 1H, J = 8.8 Hz), 7.27-7.17 (m, 3H), 6.86 (d, 1H,J = 8.8 Hz), 4.06 (t, 2H, J = 7.0 Hz), 1.72 (qt, 2H, J = 7.0 Hz), 1.38(s, 6H), 0.71 (t, 3H, 705 5-Fluoro-N4- (4-fluoro-3-methoxyphenyl)-N2-(1-n- ¹H NMR (DMSO-d6): d 10.46 (s, 1H), 10.35 (s, 1H), 8.28 (d, 1H, J= + propylindazol-5-yl)-2,4-pyrimidinediamine 4.9 Hz), 7.90 (s, 1 H),7.87 (s, 1H), 7.63 (d, 1H, J = 9.1 Hz), 7.43 (dd, 1H, J = 2.3 and 8.8Hz), 7.27-7.22 (m, 1H), 7.14 (dd, 1H, J = 1.8 and 11.1 Hz), 4.34 (t, 2H,J = 7.0 Hz), 3.60 (s, 706 N4- (3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(1-n- ¹H NMR (DMSO-d6): d 10.51 (s, 1H), 10.44 (s, 1H), 8.33 (d, 1H, J= + + propylindazol-6-yl)-2,4-pyrimidinediamine 4.9 Hz), 7.96 (s, 1H),7.77 (d, 1H, J = 2.6 Hz), 7.67 (d, 1H, J = 8.8 Hz), 7.55 (dd, 1H, J =2.6 and 8.8 Hz), 7.16 (dd, 1H, J = 2.6 and 8.8 Hz), 4.03 (t, 2H, J = 7.0Hz), 3.83 (s, 3H), 1.6 707 N4- (3,4-Dichlorophenyl)-5-fluoro-N2-(1-n-propylindazol-6-yl)- ¹H NMR (DMSO-d6): d 10.15 (s, 1H), 10.02 (s,1H), 8.30 (d, 1H, J = + + 2,4-pyrimidinediamine 4.4 Hz), 8.06 (d, 1H, J= 2.6 Hz), 7.93 (s, 1H), 7.89 (s, 1H), 7.73 (dd, 1H, J = 2.6 and 8.5Hz), 7.65 (d, 1H, J = 8.5 Hz), 7.55 (d, 1H, J = 8.8 Hz), 7.21 (d, 1H, J= 8.8 Hz), 4.07 (t, 2H, 708 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- ¹H NMR(DMSO-d6): d 10.77 (s, 1H), 10.37 (s, 1H), 10.16 (s, 1H), + +(1-n-propylindazol-6-yl)-2,4-pyrimidinediamine 8.21 (d, 1H, J = 5.3 Hz),7.89 (s, 1H), 7.87 (s, 1H), 7.61 (d, 1H, J = 8.8 Hz), 7.37 (dd, 1H, J =1.8 and 8.8 Hz), 7.20 (d, 1H, J = 8.8 Hz), 8.87 (d, 1H, J = 8.8 Hz),4.31 (t, 2H, J = 7.0 Hz) 709 5-Fluoro-N4- (4-fluoro-3-methoxyphenyl)-N2-(1-n- ¹H NMR (DMSO-d6): d 10.40 (s, 1H), 10.37 (s, 1H), 8.33 (d, 1H, J= + propylindazol-6-yl)-2,4-pyrimidinediamine 5.0 Hz), 7.96 (s, 1H),7.84 (s, 1H), 7.64 (d, 1H, J = 8.5 Hz), 7.47 (dt, 1H, J = 1.8 and 8.5Hz), 7.26-7.22 (m, 2H), 7.15 (dd, 1H, J = 11.8 and 8.8 Hz), 4.02 (t, 2H,J = 7.0 Hz), 3.55 (s, 710 N2- (1-n-Butylindazol-5-yl )-N4-(3-chloro-4-methoxyphenyl)-5- ¹H NMR (DMSO-d6): d 10.40 (s, 1H), 10.27(s, 1H), 7.92 (s, 1H), 7.82 + fluoro-2,4-pyrimidinediamine (s, 1H), 7.75(d, 1H, J = 2.3 Hz), 7.65 (d, 1H, J = 9.1 Hz), 7.54 (dd, 1H, J = 2.3 and9.1 Hz), 7.39 (d, 1H, J = 9.1 Hz), 7.09 (d, 1H, J = 9.1 Hz), 4.36 (t,2H, J = 7.3 Hz), 3.83 (s, 3H) 711 N2- (1-n-Butylindazol-5-yl)-N4-(3,4-dichlorophenyl)-5-fluoro- ¹H NMR (DMSO-d6): d 10.43 (s, 1H), 10.20(s, 1H), 8.32 (d, 1H, J = + 2,4-pyrimidinediamine 4.7 Hz), 8.00 (d, 1H,J = 2.3 Hz), 7.95 (s, 1H), 7.83 (s, 1H), 7.67 (d, 2H, J = 8.8 Hz), 7.49(d, 1H, J = 8.8 Hz), 7.41 (dd, 1H, J = 2.3 and 8.8 Hz), 4.38 (t, 2H, J =7.3 Hz), 1.79 (q, 2H, 712 N2- (1-n-Butylindazol-5-yl)-N4-(2,2-dimethyl-3-oxo-4H- ¹H NMR (DMSO-d6): d 10.75 (s, 1H), 10.28 (s,1H), 10.05 (s, 1H), + +benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.19 (d, 1H, J =4.9 Hz), 7.89 (s, 2H), 7.60 (d, 1H, J = 9.1 Hz), 7,38 (d, 1H, J = 9.1Hz), 7.20 (dd, 1H, J = 1.8 and 9.1 Hz), 7.16 (s, 1H), 6.86 (d, 1H, J =9.1 Hz), 4.35 (t, 2H, J = 7.3 Hz) 713 N2-(1-n-Butylindazol-5-yl)-5-fluoro-N4- (4-fluoro-3- ¹H NMR (DMSO-d6): d10.42 (s, 1H), 10.29 (s, 1H), 8.27 (d, 1H, J = + +methoxyphenyl)-2,4-pyrimidinediamine 4.9 Hz), 7.89 (s, 1H), 7.87 (s,1H), 7.63 (d, 1H, J = 8.8 Hz), 7.43 (dd, 1H, J = 2.3 and 8.8 Hz), 7.36(dd, 1H, J = 1.8 and 9.1 Hz), 7.28-7.23 (m, 1H), 7.13 (dd, 1H, J = 11.3and 9.1 Hz 0, 714 N2- (1-n-Butylindazol-6-yl )-N4-(3-chloro-4-methoxyphenyl)-5- ¹H NMR (DMSO-d6): d 10.27 (s, 2H), 8.30(d, 1H, J = 4.7 Hz), 7.94 (s, + fluoro-2,4-pyrimidinediamine 1H), 7.82(s, 1H), 7.77 (d, 1H, J = 2.6 Hz), 7.65 (d, 1H, J = 8.8 Hz), 7.56 (dd,1H, J = 2.6 and 8.8 Hz), 7.16 (d, 1H, J = 8.8 Hz 0, 7.11 (d, 1H, J = 8.8Hz), 4.06 (t, 2H, J = 7.3 Hz), 3 715 N2- (1-n-Butylindazol-6-yl)-N4-(3,4-dichlorophenyl)-5-fluoro- ¹H NMR (DMSO-d6): d 10.21 (s, 1H), 10.09(s, 1H), 8.32 (d, 1H, J = + 2,4-pyrimidinediamine 4.4 Hz), 8.05 (d, 1H,J = 2.3 Hz), 7.94 (s, 1H), 7.86 (s, 1H0, 7.72 (d, 1H, J = 8.8 Hz), 7.66(d, 1H, J = 8.8 Hz), 7.55 (d, 1H, J = 8.8 Hz), 7.20 (d, 1H, J = 8.8 Hz),4.11 (t, 2H, J = 7.3 716 N2- (1-n-Butylindazol-6-yl)-N4-(2,2-dimethyl-3-oxo-4H- ¹H NMR (DMSO-d6): d 11.77 (s, 1H), 10.40 (s,1H), 10.36 (s, 1H), + +benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.29 (d, 1H, J =4.9 Hz), 7.94 (s, 1H), 7.81 (s, 1H), 7.62 (d, 1H, J = 8.8 Hz), 7.23 (s,2H), 7.18 (d, 1H, J = 8.8 Hz), 6.85 (d, 1H, J = 8.8 Hz), 4.10 (t, 2H, J= 7.3 Hz), 1.67 (q, 2H, J = 7 717 N2-(1-n-Butylindazol-6-yl)-5-fluoro-N4- (4-fluoro-3- ¹H NMR (DMSO-d6): d10.42 (s, 1H), 10.37 (s, 1H), 8.33 (d, 1H, J = +methoxyphenyl)-2,4-pyrimidinediamine 4.7 Hz), 7.96 (s, 1H), 7.84 (s,1H), 7.64 (d, 1H, J = 8.8 Hz), 7.50-7.46 (m, 1H), 7.27-7.22 (m, 1H),7.16 (app t, 1H, J = 11.8 and 8.8 Hz), 4.06 (t, 2H, J = 7.3 Hz), 3.54(s, 3H), 1.65 (q, 718 N4- (3-Chloro-4-methoxyphenyl)-N2-[1- ¹H NMR(DMSO-d6): d 10.19 (s, 1H), 10.03 (s, 1H), 8.22 (d, 1H, J = +(cyclohexylmethyl)indazol-5-yl]-5-fluoro-2,4-pyrimidinediamine 4.9 Hz),7.90 (s, 1H), 7.84 (s, 1H), 7.76 (d, 1H, J = 2.6 Hz), 7.62 (d, 1H, J =9.1 Hz), 7.56 (dd, 1H, J = 2.6 and 9.1 Hz), 7.39 (dd, 1H, J = 1.8 and9.1 Hz), 7.09 (d, 1H, J = 9.1 Hz), 4.2 719 N2-[1-(Cyclohexylmethyl)indazol-5-yl]-N4- (3,4-dichlorophenyl)- ¹H NMR(DMSO-d6): d 9.69 (s, 1H), 9.38 (s, 1H), 8.17 (d, 1H, J = 3.8 +5-fluoro-2,4-pyrimidinediamine Hz), 8.07 (app d, 1H, J = 2.6 Hz), 7.92(s, 1H), 7.88 (s, 1H0, 7.78 (d, 1H, J = 8.8 Hz), 7.58 (d, 1H, J = 9.1 Hz0, 7.49-7.44 (m, 2H), 4.19 (d, 2H, J = 7.3 Hz), 1.91-1.84 (m, 1H), 1.62(m 720 N2-[1- (Cyclohexylmethyl)indazol-5-yl]-N4- (2,2-dimethyl-3-oxo-¹H 7.90 (s, 1H), 7.84 (s, 1H), 7.62 (d, 1H, J = 9.1 Hz), 7.37 (dd, 1H, J= + 4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 2.3 and 8.8Hz), 7.23 (dd, 1H, J = 2.3 and 9.1 Hz), 7.17 (s, 1H), 6.84 (d, 1H, J =9.1 Hz), 4.19 (d, 2H, J = 7.3 Hz), 1.91-1.84 (m, 1H), 1.62 (br s, 3H),1.47-1.38 (m, 2H), 1.36 (s 721 N2-[1-(Cyclohexylmethyl)indazol-5-yl)-5-fluoro-N4- (4-fluoro-3- ¹H NMR(DMSO-d6): d 10.31 (s, 1H), 10.13 (s, 1H), 8.25 (d, 1H, J = +methoxyphenyl)-2,4-pyrimidinediamine 4.9 Hz), 7.89 (s, 1H), 7.87 (s,1H), 7.62 (d, 1H, J = 8.8 Hz), 7.43 (dd, 1H, J = 2.6 and 8.8 Hz), 7.36(dd, 1H, J = 1.8 and 9.1 Hz), 7.29-7.25 (s, 1H), 7.12 (dd, 1H, J = 8.8and 11.4 Hz), 722 N4- (3-Chloro-4-methoxyphenyl)-N2-[1- ¹H NMR(DMSO-d6): d 10.12 (s, 2H), 8.26 (d, 1H, J = 4.7 Hz), 7.93 (s, + +(cyclohexylmethyl)indazol-6-yl]-5-fluoro-2,4-pyrimidinediamine 1H), 7.85(s, 1H), 7.78 (d, 1H, J = 2.6 Hz), 7.63 (d, 1H, J = 8.8 Hz), 7.58 (dd,1H, J = 2.6 and 8.8 Hz), 7.19 (d, 1H, J = 8.8 Hz), 7.11 (d, 1H, J = 8.8Hz), 3.90 (d, 2H, J = 7.3 Hz), 3 723 N2-[1-(Cyclohexylmethyl)indazol-6-yl]-N4- (3,4-dichlorophenyl)- ¹H NMR(DMSO-d6): d 10.05 (s, 1H), 9.91 (s, 1H), 8.29 (d, 1H, J = 4.1 −5-fluoro-2,4-pyrimidinediamine Hz 0, 8.05 (d, 1H, J = 2.3 Hz), 7.92 (s,1H), 7.90 (s, 1H), 7.73 (dd, 1H, J = 2.3 and 8.8 Hz), 7.63 (d, 1H, J =8.8 Hz), 7.54 (d, 1H, J = 8.8 Hz), 7.21 (d, 1H, J = 8.8 Hz), 3.93 (d,2H, 724 N2-[1- (Cyclohexylmethyl)indazol-6-yl]-N4- (2,2-dimethyl-3-oxo-¹H NMR (DMSO-d6): d 10.73 (s, 1H), 10.07 (s, 1H), 10.01 (s, 1H), +4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.22 (d, 1H, J =4.7 Hz), 7.91 (s, 1H), 7.86 (s, 1H), 7.60 (d, 1H, J = 8.8 Hz 0, 7.26(dd, 1H, J = 2.3 and 8.5 Hz), 7.22-7.19 (app m, 2H), 6.85 (d, 1H, J =8.5 Hz), 3.93 (d, 2H, J = 7.3 Hz), 1 725 N2-[1-(Cyclohexylmethyl)indazol-6-yl)-5-fluoro-N4- (4-fluoro-3- ¹H NMR(DMSO-d6): d 10.24 (s, 2H), 8.29 (d, 1H, J = 4.7 Hz), 7.95 (s, +methoxyphenyl)-2,4-pyrimidinediamine 1H), 7.86 (s, 1H), 7.63 (d, 1H, J =8.8 Hz), 7.49 (dd, 1H, J = 2.3 and 8.8 Hz), 7.28-7.24 (m, 1H), 7.19-7.12(m, 2H), 3.91 (d, 2H, J = 7.3 Hz), 3.55 (s, 3H), 1.75-1.73 (m, 1H), 1.54(br 726 N4- (3-Chloro-4-methoxyphenyl)-N2-[1- ¹H NMR (DMSO-d6): d 10.40(s, 1H), 10.26 (s, 1H), 8.26 (d, 1H, J = +(cyclobutylmethyl)indazol-5-yl]-5-fluoro-2,4-pyrimidinediamine 5.3 Hz),7.91 (s, 1H), 7.81 (s, 1H), 7.75 (d, 1H, J = 2.6 Hz), 7.68 (d, 1H, J =9.1 Hz), 7.55 (dd, 1H, J = 2.6 and 2.6 and 8.8 Hz), 7.38 (d, 1H, J = 8.8Hz), 7.09 (d, 1H, J = 9.1 Hz), 4.39 727 N2-[1-(Cyclobutylmethyl)indazol-5-yl]-N4- (3,4-dichlorophenyl)- ¹H NMR(DMSO-d6): d 10.32 (s, 1H), 10.06 (s, 1H), 8.29 (d, 1H, J = +5-fluoro-2,4-pyrimidinediamine 4.7 Hz), 8.00 (s, 1H), 7.93 (s, 1H), 7.84(s, 1H), 7.68 (d, 2H, J = 8.8 Hz), 7.49 (d, 1H, J = 8.8 Hz), 7.41 (d,1H, J = 8.8 Hz), 4.40 (d, 2H), 2.86-2.76 (m, 1H), 1.96-1.75 (m, 6H).LCMS: 728 N2-[1- (Cyclobutylmethyl)indazol-5-yl]-N4-(2,2-dimethyl-3-oxo- ¹H NMR (DMSO-d6): d 10.79 (s, 1H), 10.40 (s, 1H),10.25 (s, 1H), 8.23 +4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine (d, 1H, J = 4.9Hz), 7.88 (s, 1H0, 7.86 (s, 1H0, 7.64 (d, 1H, J = 8.8 Hz), 7.37 (d, 1H,J = 9.1 Hz), 7.21 (s, 1H), 7.18 (s, 1H), 6.86 (d, 1H, J = 9.1 Hz), 4.37(d, 1H, J = 7.0 Hz), 2.83-2 729 N2-[1-(Cyclobuylmethyl)indazol-5-yl)-5-fluoro-N4- (4-fluoro-3- ¹H NMR(DMSO-d6): d 10.48 (s, 1H), 10.36 (s, 1H), 8.29 (d, 1H, J = +methoxyphenyl)-2,4-pyrimidinediamine 5.3 Hz), 7.88 (s, 1H), 7.86 (s,1H0, 7.67 (d, 1H, J = 8.0 Hz), 7.43 (dd, 1H, J = 2.3 and 8.0 Hz), 7.35(dd, 1H, J = 1.8 and 8.8 Hz), 7.26-7.23 (m, 1H), 7.14 (dd, 1H, J = 9.1and 11.8 Hz), 730 N4- (3-Chloro-4-methoxyphenyl)-N2-[1- ¹H NMR(DMSO-d6): d 10.35 (s, 2H), 8.31 (d, 1H, J = 4.7 Hz), 7.94 (s, +(cyclobutylmethyl)indazol-6-yl]-5-fluoro-2,4-pyrimidinediamine 1 H0,7.86 (s, 1H), 7.78 (d, 1H, J = 2.3 Hz), 7.66 (d, 1H, J = 8.8 Hz), 7.57(dd, 1H, J = 2.3 and 8.8 Hz 0, 7.16 (d, 1H, J = 8.8 Hz), 7.12 (d, 1H, J= 8.8 Hz), 4.09 (d, 2H, J = 7.3 Hz), 3 731 N2-[1-(Cyclobutylmethyl)indazol-6-yl]-N4- (3,4-dichlorophenyl)- ¹H NMR(DMSO-d6): d 10.27 (s, 1H), 10.16 (s, 1H), 8.30 (d, 1H, J = +5-fluoro-2,4-pyrimidinediamine 4.4 Hz), 7.99 (d, 1H, J = 2.3 Hz), 7.88(s, 1H), 7.85 (s, 1H), 7.67 (dd, 1H, J = 2.3 and 8.8 Hz), 7.60 (d, 1H, J= 8.8 Hz), 7.51 (d, 1H, J = 8.8 Hz), 7.13 (d, 1H, J = 8.8 Hz), 4.07 (d,2H, 732 N2-[1- (Cyclobutylmethyl)indazol-6-yl]-N4- (2,2-dimethyl-3-oxo-¹H NMR (DMSO-d6): d 10.81 (s, 1H), 10.63 (s, 1H), 10.55 (s, 1H), +4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.33 (d, 1H, J =5.3 Hz), 7.94 (s, 1H), 7.81 (s, 1H), 7.64 (d, 1H, J = 8.8 Hz), 7.24-7.21(m, 2H), 7.17 (d, 1H, J = 8.5 Hz), 6.86 (d, 1H, J = 8.5 Hz), 4.12 (d,2H, J = 7.0 Hz), 2.71-2.61 (m, 733 N2-[1-(Cyclobuylmethyl)indazol-6-yl)-5-fluoro-N4- (4-fluoro-3- ¹H NMR(DMSO-d6): d 10.67 (s, 1H), 10.58 (s, 1H), 8.38 (d, 1H, J = +methoxyphenyl)-2,4-pyrimidinediamine 5.3 Hz), 7.96 (s, 1H), 7.85 (s,1H), 7.66 (d, 1H, J = 8.5 Hz), 7.48 (dd, 1H, J = 2.3 and 8.5 Hz),7.23-7.11 (m, 3H), 4.07 (d, 2H, J = 7.0 Hz), 3.51 (s, 3H), 2.67-2.57 (m,6H). LCMS: ret. 734 N4- (3-Chloro-4-methoxyphenyl)-N2-[1- ¹H NMR(DMSO-d6): d 10.05 (s, 1H), 9.91 (s, 1H), 8.31 (d, 1H, J = 5.2 +(cyclopropylmethyl)indazol-5-yl]-5-fluoro-2,4- Hz), 7.96 (s, 1H), 7.87(s, 1H), 7.80 (s, 1H), 7.72 (d, 1H, J = 8.8 Hz), pyrimidinediamine 7.60(d, 1H, J = 8.8 Hz), 7.43 (d, 1H, J = 9.1 Hz), 7.14 (d, 1H, J = 8.8 Hz),4.31 (d, 2H, J = 7.0 Hz), 3.48 (s, 735 N2-[1-(Cyclopropylmethyl)indazol-5-yl]-N4- (3,4- ¹H NMR (DMSO-d6): d 10.39 (s,1H), 10.14 (s, 1H), 8.31 (d, 1H, J = +dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine 4.7 Hz), 8.05 (d, 1H, J =2.3 Hz), 7.98 (s, 1H), 7.89 (s, 1H), 7.73 (d, 1H, J = 9.1 Hz), 7.54 (d,1H, J = 8.8 Hz), 7.45 (dd, 1H, J = 2.3 and 8.8 Hz), 4.32 (d, 2H, J = 7.0Hz), 1.34-1.24 (m 736 N2-[1- (Cyclopropylmethyl)indazol-5-yl]-N4-(2,2-dimethyl-3- ¹H NMR (DMSO-d6): d 10.85 (s, 1H), 10.46 (s, 1H), 10.29(s, 1H), + + oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine8.23 (d, 1H, J = 5.3 Hz), 7.95 (s, 1H), 7.94 (s, 1H0, 7.71 (d, 1H, J =9.1 Hz), 7.42 (dd, 1H, J = 2.3 and 9.1 Hz), 7.27 (d, 1H, J = 8.5 Hz),7.25 (s, 1H), 6.95 (d, 1H, J = 8.5 Hz), 4.32 (d, 737 N2-[1-(Cyclopropylmethyl)indazol-5-yl)-5-fluoro-N4- (4-fluoro-3- ¹H NMR(DMSO-d6): d 10.43 (s, 1H), 10.27 (s, 1H), 8.31 (d, 1H, J = +methoxyphenyl)-2,4-pyrimidinediamine 4.3 Hz), 7.95 (s, 1H), 7.94 (s,1H), 7.71 (d, 1H, J = 9.1 Hz), 7.48 (dd, 1H, J = 2.3 and 8.8 Hz), 7.41(dd, 1H, J = 2.3 and 9.1 Hz), 7.31-7.29 (m, 1H), 7.30 (dd, 1H, J = 8.8and 11.1 Hz), 738 N4- (3-Chloro-4-methoxyphenyl)-N2-[1- ¹H NMR(DMSO-d6): d 10.28 (s, 2H), 8.31 (d, 1H, J = 4.3 Hz), 7.95 (s, +(cyclopropylmethyl)indazol-6-yl]-5-fluoro-2,4- 1H), 7.96 (s, 2H), 7.87(s, 1H), 7.79 (d, 1H, J = 2.6 Hz), 7.69 (d, 1H, J = pyrimidinediamine8.8 Hz), 7.58 (dd, 1H, J = 2.6 and 9.1 Hz), 7.19 (dd, 1H, J = 1.8 and8.8 Hz), 7.11 (d, 1H, J = 9.1 Hz), 4.32 739 N2-[1-(Cyclopropylmethyl)indazol-6-yl]-N4- (3,4- ¹H NMR (DMSO-d6): d 10.21 (s,1H), 10.10 (s, 1H), 8.32 (d, 1H, J = +dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine 4.3 Hz), 8.04 (d, 1H, J =2.6 Hz), 7.93 (s, 1H), 7.91 (s, 1H), 7.71 (dd, 1H, J = 2.6 and 8.8 Hz),7.65 (d, 1H, J = 8.8 Hz), 7.54 (d, 1H, J = 8.8 Hz), 7.20 (d, 1H, J = 8.8Hz), 4.32 (d, 2H, 740 N2-[1- (Cyclopropylmethyl)indazol-6-yl]-N4-(2,2-dimethyl-3- ¹H NMR (DMSO-d6): d 10.82 (s, 1H), 10.22 (s, 1H), 10.16(s, 1H), + + oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine8.31 (d, 1H, J = 4.7 Hz), 8.00 (d, 1H, J = 0.8 Hz), 7.97 (s, 1H), 7.34(d, 1H, J = 8.8 Hz), 7.35-7.27 (m, 3H), 6.92 (d, 1H, J = 8.5 Hz), 4.32(d, 2H, J = 7.0 Hz), 1.36 (s, 6H), 1.33-1.17 (m, 741 N2-[1-(Cyclopropylmethyl)indazol-6-yl)-5-fluoro-N4- (4-fluoro-3- ¹H NMR(DMSO-d6): d 10.23 (s, 2H), 8.31 (d, 1H, J = 4.9 Hz), 7.95 (s, +methoxyphenyl)-2,4-pyrimidinediamine 1H), 7.91 (s, 1H), 7.65 (d, 1H, J =8.8 Hz), 7.48 (dd, 1H, J = 2.3 and 8.8 Hz), , 7.29-7.24 (m, 1H),7.20-7.13 (m, 3H), 4.09 (d, 2H, J = 6.7 Hz), 3.65 (s, 3H), 1.33-1.17 (m,1H), 0.55-0 742 N4- (3-Chloro-4-methoxyphenyl)-N2-(1-cyclohexylindazol-5-yl)- ¹H NMR (DMSO-d6): d 10.35 (s, 1H), 10.20 (s,1H), 8.24 (d, 1H, J = + + 5-fluoro-2,4-pyrimidinediamine 5.3 Hz), 7.92(s, 1H), 7.81 (s, 1H), 7.74 (d, 1H, J = 2.6 Hz), 7.71 (d, 1H, J = 8.1Hz), 7.55 (dd, 1H, J = 2.6 and 8.8 Hz), 7.36 (dd, 1H, J = 1.8 and 8.8Hz), 7.09 (d, 1H, J = 8.1 Hz), 4.5 743 N2-(1-Cyclohexylindazol-5-yl)-N4- (3,4-dichlorophenyl)-5- ¹H NMR (DMSO-d6):d 10.26 (s, 1H), 9.99 (s, 1H), 8.23 (d, 1H, J = 4.9 +fluoro-2,4-pyrimidinediamine Hz), 7.96 (s, 1H), 7.89 (s, 1H), 7.80 (s,1H), 7.66 (d, 1H, J = 8.1 Hz), 7.61 (app s, 1H), 7.45 (d, 1H, J = 9.1Hz), 7.34 (d, 1H, J = 9.1 Hz), 4.53-4.49 (m, 1H), 1.87-1.78 (m, 6H),1.67 744 N2- (1-Cyclohexylindazol-5-yl)-N4- (2,2-dimethyl-3-oxo-4H- ¹HNMR (DMSO-d6): d 10.80 (s, 1H), 10.36 (s, 1H), 10.15 (s, 1H), + +benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.21 (d, 1H, J =4.9 Hz), 7.89 (s, 1H), 7.86 (s, 1H), 7.64 (d, 1H, J = 9.4 Hz), 7.36 (dd,1H, J = 2.3 and 8.8 Hz), 7.18 (d, 1H, J = 2.3 Hz), 6.86 (d, 1H, J = 9.4Hz), 4.53-4.49 (m, 1H), 1.89 745 N2-(1-Cyclohexylindazol-5-yl)-5-fluoro-N4- (4-fluoro-3- ¹H NMR (DMSO-d6): d10.26 (s, 1H), 10.07 (s, 1H), 8.22 (d, 1H, J = +methoxyphenyl)-2,4-pyrimidinediamine 5.0 Hz), 7.90 (s, 1H), 7.89 (s,1H), 7.67 (d, 1H, J = 8.8 Hz), 7.44 (dd, 1H, J = 8.5 Hz), 7.34 (dd, 1H,J = 1.8 and 8.8 Hz), 7.28-7.24 (m, 1H), 7.15 (dd, 1H, J = 8.8 and 11.1Hz), 4.53-4.4 746 N4- (3-Chloro-4-methoxyphenyl)-N2-(1-cyclohexylindazol-6-yl)- ¹H NMR (DMSO-d6): d 10.21 (s, 1H), 10.19 (s,1H), 8.28 (d, 1H, J = + 5-fluoro-2,4-pyrimidinediamine 4.9 Hz), 7.95 (s,1H), 7.86 (d, 1H, J = 2.6 Hz), 7.84 (s, 1H), 7.66 (d, 1H, J = 8.5 Hz),7.59 (dd, 1H, J = 2.6 and 9.1 Hz), 7.21 (dd, 1H, J = 1.8 and 8.5 Hz),7.06 (d, 1H, J = 9.1 Hz), 4.19 747 N2- (1-Cyclohexylindazol-6-yl)-N4-(3,4-dichlorophenyl)-5- ¹H NMR (DMSO-d6): d 10.05 (s, 1H), 9.88 (s, 1H),8.29 (d, 1H, J = 4.9 + fluoro-2,4-pyrimidinediamine Hz), 8.11 (d, 1H, J= 2.6 Hz), 7.93 (s, 1H), 7.92 (s, 1H), 7.78 (dd, 1H, J = 2.6 and 8.8Hz), 7.64 (d, 1H, J = 8.5 Hz), 7.51 (d, 1H, J = 8.8 Hz), 7.22 (dd, 1H, J= 1.7 and 8.5 Hz), 4.19 748 N2- (1-Cyclohexylindazol-6-yl)-N4-(2,2-dimethyl-3-oxo-4H- ¹H NMR (DMSO-d6): d 10.76 (s, 1H), 10.25 (s,1H), 10.18 (s, 1H), +benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.24 (d, 1H, J =4.9 Hz), 7.94 (s, 1H), 7.83 (s, 1H), 7.63 (d, 1H, J = 8.5 Hz), 7.31-7.22(m, 3H), 6.80 (d, 1H, J = 8.5 Hz), 4.23-4.12 (m, 1H), 1.85-1.77 (m, 6H),1.65-1.62 (m, 1H), 1.38 (s, 749 N2-(1-Cyclohexylindazol-6-yl)-5-fluoro-N4- (4-fluoro-3- ¹H NMR (DMSO-d6): d10.02 (s, 1H), 9.95 (s, 1H), 8.26 (d, 1H, J = 4.3 +methoxyphenyl)-2,4-pyrimidinediamine Hz), 7.93 (s, 2H), 7.83 (s, 1H),7.63 (d, 1H, J = 8.8 Hz), 7.55 (dd, 1H, J = 2.6 and 8.8 HzO, 7.31-7.28(m, 1H), 7.18 (d, 1H, J = 8.8 Hz), 7.12 (dd, 1H, J = 8.8 and 11.4 Hz),4.11-4.00 750 N4- (3,4-Dichlorophenyl)-5-fluoro-N2-(3-methylindazol-6-yl)- ¹H NMR (DMSO-d6): d 12.23 (s, 1H), 9.53 (s, 1H),9.36 (s, 1H), 8.14 + + 2,4-pyrimidinediamine (d, 1H, J = 3.5 Hz), 8.10(d, 1H, J = 2.7 Hz), 7.88 (s, 1H), 7.86 (dd, 1H, J = 2.7 and 8.8 Hz),7.47 (d, 2H, J = 8.8 Hz), 7.16 (dd, 1H, J = 1.8 and 8.8 Hz), 2.36 (s,3H). LCMS: ret. time 751 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- ¹H NMR(DMSO-d6): d 10.62 (s, 1H), 9.63 (s, 1H), 9.44 (s, 1H), 8.13 + +(3-methylindazol-6-yl)-2,4-pyrimidinediamine (d, 1H, J = 41. Hz), 7.84(s, 1H), 7.50 (d, 1H, J = 8.8 Hz), 7.36 (dd, 1H, J = 2.3 and 8.5 Hz),7.31 (d, 1H, J = 2.3 Hz), 7.24 (dd, 1H, J = 1.8 and 8.8 Hz), 6.89 (d,1H, J = 8.5 Hz), 2.41 752 N4- (3-Chloro-4-methoxyphenyl)-N2-(1,3-dimethylindazol-6-yl)- ¹H NMR (DMSO-d6): d 10.49 (s, 1H), 10.43 (s,1H), 8.33 (d, 1H, J = + + 5-fluoro-2,4-pyrimidinediamine 5.3 Hz), 7.77(d, 1H, J = 2.6 Hz), 7.67 (d, 1H, J = 1.2 Hz), 7.62 (d, 1H, J = 8.8 Hz),7.55 (dd, 1H, J = 2.6 and 8.8 Hz), 7.10 (d, 1H, J = 8.8 Hz), 7.09 (d,1H, J = 8.8 Hz), 3.83 (s, 3H), 753 N4- (3,4-Dichlorophenyl)-N2-(1,3-dimethylindazol-6-yl)-5- ¹H NMR (DMSO-d6): d 9.65 (s, 1H), 9.50 (s,1H), 8.22 (d, 1H, J = 3.5 + + fluoro-2,4-pyrimidinediamine H), 8.12 (d,1H, J = 2.3 Hz), 7.91 (d, 1H, J = 1.8 Hz), 7.79 (dd, 1H, J = 2.3 and 8.8Hz), 7.52 (dd, 2H, J = 2.3 and 8.8 Hz), 7.18 (dd, 1H, J = 1.8 and 8.8Hz), 3.69 (s, 3H), 2.39 (s, 3H) 754 N2- (1,3-Dimethylindazol-6-yl)-N4-(2,2-dimethyl-3-oxo-4H- ¹H NMR (DMSO-d6): d 10.72 (s, 1H), 10.25 (s,2H), 8.26 (d, 1H, J = + + +benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 4.9 Hz), 7.72 (s,1H), 7.57 (d, 1H, J = 8.5 Hz), 7.25 (dd, 1H, J = 2.3 and 8.5 Hz), 7.22(app s, 1H), 7.14 (dd, 1H, J = 2.3 and 8.5 Hz), 6.87 (d, 1H, J = 8.5Hz), 3.37 (s, 3H), 2.40 (s, 3H 755 N2-(1,3-Dimethylindazol-6-yl)-5-fluoro-N4- (4-fluoro-3- ¹H NMR (DMSO-d6): d10.14 (s, 2H), 8.28 (d, 1H, J = 3.7 Hz), 7.79 (d, + +methoxyphenyl)-2,4-pyrimidinediamine 1H, J = 1.8 Hz), 7.57 (d, 1H, J =8.5 Hz), 7.48 (dd, 1H, J = 2.3 and 8.5 Hz), 7.31-7.26 (m, 1H), 7.17 (dd,1H, J = 8.8 and 11.4 Hz), 7.10 (dd, 1H, J = 1.8 and 8.8 Hz), 3.66 (s,3H), 3.6 756 N4- (3-Chloro-4-methoxyphenyl)-N2-(1,6-dimethylindazol-5-yl)- ¹H NMR (DMSO-d6): d 10.44 (s, 1H), 9.89 (s,1H), 8.21 (d, 1H, J = 5.6 + 5-fluoro-2,4-pyrimidinediamine Hz), 7.97 (s,1H), 7.70 (s, 1H), 7.62 (s, 1H), 7.58 (s, 1H), 7.46 (d, 1H, J = 8.5 Hz),6.91 (d, 1H, J = 8.5 Hz), 4.00 (s, 3H), 3.75 (s, 3H), 2.32 (s, 3H).LCMS: ret. time: 9.25 min.; 757 N4- (3,4-Dichlorophenyl)-N2-(1,6-dimethylindazol-5-yl)-5- ¹H NMR (DMSO-d6): d 10.34 (s, 1H), 9.70(s, 1H), 8.24 (d, 1H, J = 4.7 + fluoro-2,4-pyrimidinediamine Hz), 7.97(s, 1H), 7.87 (s, 1H), 7.68 (s, 1H), 7.58 (s, 1H), 7.55 (d, 1H, J = 8.5Hz), 7.37 (d, 1H, J = 8.5 Hz), 4.01 (s, 3H), 2.32 (s, 3H). LCMS: ret.time: 11.58 min.; purity: 91%; 758 N2- (1,6-Dimethylindazol-5-yl)-N4-(2,2-dimethyl-3-oxo-4H- ¹H NMR (DMSO-d6): d 10.70 (s, 1H), 10.51 (s,1H), 8.16 (d, 1H, J = + +benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 4.9 Hz), 7.95 (s,1H), 7.74 (s, 1H), 7.55 (s, 1H), 7.17 (d, 1H, J = 8.5 Hz), 6.69 (d, 1H,J = 8.5 Hz), 4.00 (s, 3H), 2.34 (s, 3H), 1.31 (s, 6H). LCMS: ret. time:8.24 min.; purity: 96%; 759 N2- (1,6-Dimethylindazol-5-yl)-5-fluoro-N4-(4-fluoro-3- ¹H NMR (DMSO-d6): d 10.42 (s, 1H), 9.84 (s, 1H), 8.18 (d,1H, J = 3.9 + methoxyphenyl)-2,4-pyrimidinediamine Hz), 7.96 (s, 1H),7.74 (s, 1H), 7.57 (s, 1H), 7.45 (d, 1H, J = 8.5 Hz), 7.20 (m, 1H), 6.97(m, 1H), 4.02 (s, 3H), 3.55 (s, 3H), 2.33 (s, 3H). LCMS: ret. time: 9.33min.; purity: 96%; 760 N4- (3,4-Dichlorophenyl)-N2-(2-ethylindazol-6-yl)-5-fluoro-2,4- ¹H NMR (DMSO-d6): d 10.25 (s, 1H),10.06 (s, 1H), 8.36 (d, 1H, J = + + pyrimidinediamine 1.8 Hz), 8.30 (d,1H, J = 4.4 Hz), 8.03 (d, 1H, J = 2.3 Hz), 7.86 (s, 1H), 7.82 (dd, 1H, J= 2.6 and 8.8 Hz), 7.66 (d, 1H, J = 8.8 Hz), 7.53 (d, 1H, J = 8.8 Hz),7.14 (dd, 1H, J = 1.8 and 761 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2- (2- ¹H NMR (DMSO-d6): d10.57 (s, 1H), 9.51 (s, 1H), 9.30 (s, 1H), 8.21 + + −ethylindazol-6-yl)-5-fluoro-2,4-pyrimidinediamine (s, 1H), 8.12 (d, 1H,J = 4.1 Hz), 8.07 (s, 1H), 7.51 (d, 1H, J = 9.1 Hz), 7.40 (d, 1H, J =2.3 Hz), 7.27 (dd, 1H, J = 2.3 and 8.8 Hz), 7.11 (dd, 1H, J = 1.8 and9.1 Hz), 6.89 (d, 1H, J = 762 N4- (3,4-Dichlorophenyl)-5-fluoro-N2-(2-n-propylindazol-5-yl)- ¹H NMR (DMSO-d6): d 10.14 (s, 1H), 9.82 (s,1H), 8.25 (d, 1H, J = 4.4 + + 2,4-pyrimidinediamine Hz), 8.22 (s, 1H),8.06 (d, 1H, J = 2.3 Hz), 7.83 (s, 1H), 7.74 (dd, 1H, J = 2.3 and 9.1Hz), 7.57 (d, 1H, J = 9.1 Hz), 7.50 (d, 1H, J = 9.1 Hz), 7.27 (dd, 1H, J= 2.3 and 9.1 Hz), 4.34 763 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- ¹H NMR(DMSO-d6): d 10.77 (s, 1H), 10.33 (s, 1H), 10.07 (s, 1H), + +(2-n-propylindazol-5-yl)-2,4-pyrimidinediamine 8.20 (d, 1H, J = 5.3 Hz),8.15 (s, 1H), 7.81 (s, 1H), 7.54 (d, 1H, J = 9.1 Hz), 7.23-7.18 (m, 3H),6.86 (d, 1H, J = 9.1 Hz), 4.32 (t, 2H, J = 7.3 Hz), 1.90 (sextet, 2H, J= 7.3 Hz), 1.36 (s, 764 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- ¹H NMR(DMSO-d6): d 10.56 (s, 1H), 9.29 (s, 1H), 9.09 (s, 1H), 8.17 + +(2-n-propylindazol-6-yl)-2,4-pyrimidinediamine (d, 1H, J = 0.8 Hz), 8.13(d, 1H, J = 0.8 Hz), 8.09 (d, 1H, J = 3.8 Hz), 7.48 (d, 1H, J = 9.1 Hz),7.41 (d, 1H, J = 2.3 Hz), 7.29 (dd, 1H, J = 2.3 and 9.1 Hz), 7.12 (dd,1H, J = 2.3 and 8 765 N4- (3,4-Dichlorophenyl)-5-fluoro-N2-(2-n-propylindazol-6-yl)- ¹H NMR (DMSO-d6): d 9.93 (s, 1H), 9.67 (s,1H), 8.28 (s, 1H), 8.24 (d, + + 2,4-pyrimidinediamine 1H, J = 4.1 Hz),8.05 (d, 1H, J = 2.3 Hz), 7.91 (s, 1H), 7.88 (dd, 1H, J = 2.6 and 8.8Hz), 7.61 (d, 1H, J = 8.8 Hz), 7.51 (d, 1H, J = 8.8 Hz), 7.15 (d, 1H, J= 8.8 Hz), 4.28 (t, 2H, J 766 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 10.69 (s, 1H), 10.09 (s, 1H), 9.88 (s, 1H), 8.21 + + −(1-methylindazol-6-yl)-2,4-pyrimidinediamine DL-Camphor-1- (d, 1H, J =4.7 Hz), 7.91 (d, 1H, J = 0.8 Hz), 7.83 (s, 1H), 7.61 (d, 1H, sulfonicAcid Salt J = 8.5 Hz), 7.29 (dd, 1H, J = 2.3 and 8.5 Hz), 7.17 (dd, 1H,J = 2.3 an d8.5 Hz), 7.13 (d, 1H, J = 2.3 Hz), 6.85 (d, 1H, J = 8.5 Hz),3.80 (s, 3H), 2.87 (d, 1H, AB qt, J = 14.6 Hz), 2.26-2.18 (m, 1H), 1.92(br t, 1H, J = 4.7 Hz), 1.88-1.83 (m, 2H), 1.38 (s, 6H), 1.32-1.21 (,2H), 1.03 (s, 3H), 0.73 (s, 3H). LCMS: ret. time: 9.53 min.; purity:94%; MS (m/e): 434 (MH+) 767 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- ¹H NMR(DMSO-d6): d 10.70 (s, 1H), 10.22 (s, 1H), 10.00 (s, 1H), + + −(1-methylindazol-6-yl)-2,4-pyrimidinediamine Ethanesulfonic 8.24 (d, 1H,J = 4.9 Hz), 7.92 (d, 1H, J = 0.8 Hz), 7.80 (s, 1H), 7.63 (d, Acid Salt1H, J = 8.8 Hz), 7.28 (dd, 1H, J = 2.3 and 8.8 Hz), 7.16 (d, 1H, J = 1.8and 8.5 Hz), 7.11 (d, 1H, J = 2.3 Hz), 6.8 768 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- ¹H NMR(DMSO-d6): d 10.69 (s, 1H), 10.17 (s, 1H), 9.92 (s, 1H), 8.21 + + −(1-methylindazol-6-yl)-2,4-pyrimidinediamine p- (d, 1H, J = 4.7 Hz),7.92 (d, 1H, J = 0.8 Hz), 7.81 (s, 1H), 7.62 (d, 1H,Hydroxybenzenesulfonic Acid Salt J = 8.5 Hz), 7.38 (td, 2H, J = 2.6 and8.8 Hz), J = 7.28 (dd, 1H, J = 2.3 and 8.5 Hz), 7.16 (d, 1H, J = 1.8 and8 769 N4- (2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- ¹HNMR (DMSO-d6): d 10.70 (s, 1H), 10.28 (s, 1H), 10.00 (s, 1H), + + −(1-methylindazol-6-yl)-2,4-pyrimidinediamine Benzenesulfonic 8.22 (d,1H, J = 4.9 Hz), 7.94 (d, 1H, J = 0.8 Hz), 7.78 (s, 1H), 7.64 (d, AcidSalt 1H, J = 8.8 Hz), 7.60-7.56 (m, 2H), 7.33-7.26 (m, 4H), 7.15 (d, 1H,J = 1.8 and 8.5 Hz), 7.10 (d, 1H, J = 2.3 Hz), 770 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- ¹H NMR(DMSO-d6): d 10.74 (s, 1H), 10.21 (s, 2H), 8.26 (d, 1H, J = + + −(1-methylindazol-6-yl)-2,4-pyrimidinediamine Hydrochloric Acid 4.9 Hz),7.92 (d, 1H, J = 0.8 Hz), 7.82 (s, 1H), 7.62 (d, 1H, J = 8.8 Hz), Salt7.27 (dd, 1H, J = 2.3 and 8.5 Hz), 7.21 (d, 1H, J = 2.3 Hz), 7.18 (dd,1H, J = 1.8 and 8.5 Hz), 6.86 (d, 1H, J = 771 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1- (2- ¹H NMR (DMSO-d6): d 10.18 (s,1H), 9.91 (s, 1H), 8.21 (d, 1H, J = 4.7 + + −methoxyethyl)indazol-5-yl]-2,4-pyrimidinediamine Hz), 7.98 (d, 1H, J =2.3 Hz), 7.90 (s, 1H), 7.81 (s, 1H), 7.66 (app d, 1H, J = 8.8 Hz), 7.60(d, 1H, J = 9.1 Hz), 7.46 (d, 1H, J = 9.1 Hz), 7.37 (dd, 1H, J = 2.3 and8.8 Hz), 4.48 (t, 772 N4- (3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1- (2-¹H NMR (DMSO-d6): d 10.45 (s, 1H), 10.33 (s, 1H), 8.27 (d, 1H, J = + + −methoxyethyl)indazol-5-yl]-2,4-pyrimidinediamine 4.9 Hz), 7.93 (s, 1H),7.81 (d, 1H, J = 1.5 Hz), 7.74 (d, 1H, J = 2.3 Hz), 7.65 (d, 1H, J = 8.8Hz), 7.54 (dd, 1H, J = 2.3 and 9.1 Hz), 7.37 (dd, 1H, J = 2.6 and 9.1Hz), 7.10 (d, 1H, J = 773 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- ¹H NMR(DMSO-d6): d 10.78 (s, 1H), 10.35 (s, 1H), 10.19 (s, 1H), + + − [1-(2-methoxyethyl)indazol-5-yl]-2,4-pyrimidinediamine 8.21 (d, 1H, J = 4.9Hz), 7.90 (s, 1H), 7.87 (s, 1H), 7.60 (d, 1H, J = 8.8 Hz), 7.36 (dd, 1H,J = 1.8 and 8.8 Hz), 7.21 (dd, 1H, J = 1.8 and 8.5 Hz), 7.17 (s, 1H),6.87 (d, 1H, J = 8.5 Hz), 774 5-Fluoro-N4-(4-fluoro-3-methoxyphenyl)-N2-[1- (2- ¹H NMR (DMSO-d6): d 10.19 (s, 1H),9.93 (s, 1H), 8.20 (d, 1H, J = 4.7 + + −methoxyethyl)indazol-5-yl]-2,4-pyrimidinediamine Hz), 7.90 (s, 2H), 7.61(d, 1H, J = 8.8 Hz), 7.44 (dd, 1H, J = 2.6 and 8.8 Hz), 7.37 (dd, 1H, J= 2.0 and 8.8 Hz), 7.29-7.26 (m, 1H), 7.13 (dd, 1H, J = 8.8 and 11.1Hz), 4.53 (t, 2H, J 775 N4- (3,4-Dichlorophenyl)-5-fluoro-N2-[1- (2- ¹HNMR (DMSO-d6): d 10.08 (s, 1H), 9.96 (s, 1H), 8.26 (d, 1H, J = 4.4 + + −methoxyethyl)indazol-6-yl]-2,4-pyrimidinediamine Hz), 8.03 (d, 1H, J =2.3 Hz), 7.91 (d, 1H, J = 0.8 Hz), 7.82 (s, 1H), 7.70 (dd, 1H, J = 2.3and and 8.8 Hz), 7.60 (d, 1H, J = 8.8 Hz), 7.49 (d, 1H, J = 8.8 Hz),7.19 (dd, 1H, J = 1.8 a 776 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1- (2- ¹H NMR (DMSO-d6): d 10.02(br s, 2H), 8.24 (d, 1H, J = 4.7 Hz), 7.95 + + −methoxyethyl)indazol-6-yl]-2,4-pyrimidinediamine (d, 1H, J = 0.8 Hz),7.83 (s, 1H), 7.79 (d, 1H, J = 2.6 Hz), 7.63 (d, 1H, J = 8.8 Hz), 6.59(dd, 1H, J = 2.6 and 9.1 Hz), 7.21 (dd, 1H, J = 1.8 and 8.8 Hz), 7.09(d, 1H, J = 9.1 Hz), 4.2 777 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- ¹H NMR(DMSO-d6): d 10.71 (s, 1H), 10.18 (br s, 2H), 8.20 (d, 1H, J = + + − [1-(2-methoxyethyl)indazol-6-yl]-2,4-pyrimidinediamine 4.9 Hz), 7.91 (d,1H, J = 0.8 Hz), 7.75 (s, 1H), 7.57 (d, 1H, J = 8.5 Hz), 7.23-7.15 (m,3H), 6.81 (d, 1H, J = 8.8 Hz), 4.24 (t, 2H, J = 5.3 Hz), 3.61 (t, 3H, J= 5.3 Hz), 3.06 (s, 3H), 778 5-Fluoro-N4-(4-fluoro-3-methoxyphenyl)-N2-[1- (2- ¹H NMR (DMSO-d6): d 9.92 (br s,2H), 8.23 (d, 1H, J = 4.4 Hz), 7.94 + −methoxyethyl)indazol-6-yl]-2,4-pyrimidinediamine (d, 1H, J = 0.8 Hz),7.91 (s, 1H), 7.59 (d, 1H, J = 8.5 Hz), 7.48 (dd, 1H, J = 2.6 and 8.8Hz), 7.34-7.30 (m, 1H), 7.21 (dd, 1H, J = 1.8 and 8.8 Hz), 7.15 (dd, 1H,J = 8.8 and 11.1 Hz), 779 N4- (3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-(1- ¹H NMR (DMSO-d6): d 10.39 (s, 1H), 10.27 (s, 1H), 8.26 (d, 1H, J = +methylethyl)indazol-5-yl]-2,4-pyrimidinediamine 4.9 Hz), 7.93 (s, 1H),7.81 (d, 1H, J = 1.4 Hz), 7.74 (d, 1H, J = 2.3 Hz), 6.67 (d, H, J = 9.1Hz), 7.54 (dd, 1H, J = 2.3 and 9.1 Hz), 7.37 (dd, 1H, J = 1.8 and 8.8Hz), 7.09 (d, 1H, J = 780 N4- (3,4-Dichlorophenyl)-5-fluoro-N2-[1-(1-methylethyl)indazol- ¹H NMR (DMSO-d6): d 10.20 (s, 1H), 9.91 (s, 1H),8.26 (d, 1H, J = + 5-yl]-2,4-pyrimidinediamine 4.7 Hz), 8.02 (d, 1H, J =2.3 Hz), 7.94 (s, 1H), 7.86 (s, 1H), 7.68 (d, 1H, J = 8.8 Hz), 7.66 (d,1H, J = 9.1 Hz), 7.50 (d, 1H, J = 8.8 Hz), 7.41 (dd, 1H, J = 1.8 and 9.1Hz), 4.95 (q, 1H, 781 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- ¹H NMR(DMSO-d6): d 10.76 (s, 1H), 10.32 (s, 1H), 10.11 (s, 1H), + [1-(1-methylethyl)indazol-5-yl]-2,4-pyrimidinediamine 8.19 (d, 1H, J = 5.3Hz), 7.90 (s, 1H), 7.89 (s, 1H), 7.62 (d, 1H, J = 8.8 Hz), 7.36 (dd, 1H,J = 1.8 and 8.8 Hz), 7.19 (d, 2H, J = 8.9 Hz), 6.87 (d, 1H, J = 8.8 Hz),4.91 (q, 1H, J = 6.4 H 782 5-Fluoro-N4-(4-fluoro-3-methoxyphenyl)-N2-[1- (1- ¹H NMR (DMSO-d6): d 10.35 (s, 1H),10.21 (s, 1H), 8.25 (d, 1H, J = +methylethyl)indazol-5-yl]-2,4-pyrimidinediamine 4.9 Hz), 7.90 (s, 1H),7.88 (s, 1H), 7.65 (d, 1H, J = 8.1 Hz), 7.43 (dd, 1H, j = 2.3 and 8.8Hz), 7.35 (dd, 1H, J = 1.8 and 8.8 Hz), 7.26-7.22 (m, 1H), 7.14 (dd, 1H,J = 8.8 and 11.1 Hz), 783 N4- (3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-(1- ¹H NMR (DMSO-d6): d 10.10 (s, 2H), 8.25 (d, 1H, J = 4.7 Hz), 7.93(s, + methylethyl)indazol-6-yl]-2,4-pyrimidinediamine 1H), 7.86 (s, 1H),7.78 (d, 1H, J = 2.3 Hz), 7.64 (d, 1H, J = 8.8 Hz), 7.56 (dd, 1H, J =2.3 and 8.8 Hz), 7.18 (d, 1H, J = 8.8 Hz), 7.10 (d, 1H, J = 8.9 Hz),4.45 (q, 1H, J = 6.4 Hz), 784 N4- (3,4-Dichlorophenyl)-5-fluoro-N2-[1-(1-methylethyl)indazol- ¹H NMR (DMSO-d6): d 10.06 (s, 1H), 9.93 (s, 1H),8.30 (d, 1H, J = + 6-yl]-2,4-pyrimidinediamine 4.3 Hz), 8.06 (d, 1H, J =2.3 Hz), 7.93 (s, 2H), 7.76 (dd, 1H, J = 2.3 and 8.8 Hz), 7.64 (d, 1H, J= 8.8 Hz), 7.54 (d, 1H, J = 8.8 Hz), 7.21 (dd, 1H, J = 1.8 and 8.8 Hz),4.55 (q, 1H, J = 6 785 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- ¹H NMR(DMSO-d6): d 10.76 (s, 1H), 10.14 (s, 2H), 8.24 (d, 1H, J = + [1-(1-methylethyl)indazol-6-yl]-2,4-pyrimidinediamine 4.9 Hz), 7.93 (s,1H), 7.88 (s, 1H), 7.61 (d, 1H, J = 8.8 Hz), 7.27-7.16 (m, 3H), 6.88 (d,1H, J = 8.8 Hz), 4.50 (q, 1H, J = 6.4 Hz), 1.37 (d, 6H, J = 6.4 Hz),1.35 (s, 6H). LCMS: ret. t 786(S)-N4-[2-Methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl]-5-fluoro- ¹H NMR(DMSO-d6): d 10.77 (s, 1H), 10.14 (s, 1H), 9.93 (s, 1H0, 8.22 + N2-[1-(1-methylethyl)indazol-6-yl]-2,4-pyrimidinediamine (d, 1H, J = 4.7 Hz),7.93 (s, 1H), 7.92 (s, 1H), 7.60 (d, 1H, J = 8.5 Hz), 7.27 (dd, 1H, J =2.3 and 8.5 Hz 0, 7.21-7.16 (m, 2H), 6.90 (d, 1H, J = 8.5 Hz), 4.65 (qt,1H, J = 6.7 Hz), 4.4 787 N2-[1- (3-Acetyloxypropyl)indazol-5-yl]-N4-(3,4- 1H NMR (DMSo-d6): d 10.17 (s, 1H), 9.90 (s, 1H), 8.21 (d, 1H, J= + + − dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine 4.7 Hz), 7.97 (d,1H, J = 2.3 Hz), 7.90 (dd, 1H, J = 2.3 and 8.8 Hz), 7.59 (d, 1H, J = 8.8Hz), 7.47 (d, 1H, J = 8.8 Hz), 7.38 (dd, 1H, J = 2.0 and 8.8 Hz), 4.41(d, 2H, J = 6.7 Hz), 3.88 788 N2-[1-(3-Acetyloxypropyl)indazol-5-yl]-N4- (3-chloro-4- 1H NMR (DMSo-d6): d10.32 (s, 1H), 10.19 (s, 1H), 8.24 (d, 1H, J = + + −methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 5.3 Hz), 7.93 (s, 1H),7.85 (s, 1H), 7.74 (d, 1H, J = 2.3 Hz), 7.63 (d, 1H, J = 8.8 Hz), 7.54(dd, 1H, J = 2.3 and 9.1 Hz), 7.40 (dd, 1H, J = 2.3 and 8.8 Hz), 7.09(d, 1H, J = 9.1 Hz), 4. 789 N2-[1-(3-Acetyloxypropyl)indazol-5-yl]-5-fluoro-N4- (4-fluoro-3- 1H NMR(DMSO-d6): d 10.31 (s, 1H), 10.15 (s, 1H), 8.24 (d, 1H, J = + + −methoxyphenyl)-2,4-pyrimidinediamine 4.7 Hz), 7.91 (s, 2H), 7.61 (d, 1H,J = 8.8 Hz), 7.44 (dd, 1H, J = 2.3 and 8.8 Hz), 7.38 (dd, 1H, J = 1.8and 9.1 Hz), 7.27-7.25 (m, 1H), 7.15 (dd, 1H, J = 8.8 and 11.1 Hz), 4.45(t, 2H, J 790 N2-[1- (3-Acetyloxypropyl)indazol-6-yl]-N4- (3,4- 1H NMR(DMSO-d6): d 9.96 (s, 1H), 9.83 (s, 1H), 8.27 (d, 1H, J = 4.1 + + −dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine Hz), 8.09 (d, 1H, J = 2.3Hz), 7.94 (s, 1H), 7.92 (s, 1H), 7.75 (dd, 1H, J = 2.3 and 8.8 Hz), 7.63(d, 1H, J = 8.8 Hz), 7.53 (d, 1H, J = 8.8 Hz), 7.23 (dd, 1H, J = 1.8 and8.8 Hz), 4.20 791 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 10.68 (s, 1H), 9.84 (s, 1H), 9.74 (s, 1H), 8.18 + + − [1-(3-hydroxypropyl)indazol-6-yl]-2,4-pyrimidinediamine (d, 1H, J = 4.4Hz), 7.90 (s, 1H), 7.56 (s, 1H), 7.58 (d, 1H, J = 8.8 Hz), 7.32-7.24 (m,3H), 6.85 (d, 1H, J = 8.8 Hz), 4.20 (t, 2H, J = 6.7 Hz), 3.29 (t, 2H, J= 6.4 Hz), 1.87 (app q, 2H 792 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1- (3- 1H NMR (DMS0-d6): d 10.42(s, 1H), 10.30 (s, 1H), 8.26 (d, 1H, J = + + − +methoxypropyl)indazol-5-yl]-2,4-pyrimidinediamine 5.2 Hz), 7.93 (s, 1H),7.82 (d, 1H, J = 1.8 Hz), 7.74 (d, 1H, J = 2.3 Hz), 7.60 (d, 1H, J = 9.1Hz), 7.53 (dd, 1H, J = 2.3 and 9.1 Hz), 7.38 (dd, 1H, J = 1.8 and 9.1Hz), 7.09 (d, 1H, J = 9 793 N4- (3,4-Dichlorophenyl)-5-fluoro-N2-[1- (3-1H NMR (DMSO-d6): d 10.36 (s, 1H), 10.13 (s, 1H), 8.30 (d, 1H, J = + + −methoxypropyl)indazol-5-yl]-2,4-pyrimidinediamine 5.0 Hz), 8.01 (d, 1H,J = 2.3 Hz), 7.95 (s, 1H), 7.86 (s, 1H), 7.68 (dd, 1H, J = 2.3 and 8.8Hz), 7.61 (d, 1H, J = 9.1 Hz), 7.51 (d, 1H, J = 8.8 Hz), 7.41 (dd, 1H, J= 1.8 and 9.1 Hz), 4.4 794 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 10.77 (s, 1H), 10.42 (s, 1H), 10.27 (s, 1H), + + − [1-(3-methoxypropyl)indazol-5-yl]-2,4-pyrimidinediamine 8.23 (d, 1H, J =4.3 Hz), 7.90 (s, 1H), 7.88 (s, 1H), 7.56 (d, 1H, J = 8.8 Hz), 7.37 (dd,1H, J = 1.8 and 8.8 Hz), 7.21 (app d, 2H, J = 9.1 Hz), 6.87 (d, 1H, J =9.1 Hz), 4.39 (t, 2H, J = 6. 795 (S)-5-Fluoro-N2-[1-(3-methoxypropyl)indazol-5-yl]-N4- (2- 1H NMR (DMSO-d6): d 10.73 (s,1H), 10.32 (s, 1H), 10.15 (s, 1H), + + −methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- 8.17 (d, 1H, J = 4.9 Hz),7.85 (s, 1H), 7.83 (s, 1H), 7.51 (d, 1H, J = 8.8 pyrimidinediamine Hz),7.33 (dd, 1H, J = 2.1 and 9.1 Hz), 7.16 (dd, 2H, J = 2.3 and 9.1 Hz),6.84 (d, 1H, J = 8.8 Hz), 4.60 (qt, 1H, 796 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1- (3- 1H NMR (DMSO-d6): d 10.16(s, 2H), 8.27 (d, 1H, J = 4.7 Hz), 7.95 (d, + + −methoxypropyl)indazol-6-yl]-2,4-pyrimidinediamine 1H, J = 0.8 Hz), 7.80(s, 1H), 7.78 (d, 1H, J = 8.8 Hz), 7.65 (d, 1H, J = 2.3 and 9.1 Hz),7.58 (dd, 1H, J = 2.3 and 9.1 Hz), 7.20 (dd, 1H, J = 1.8 an 8.8 Hz),7.09 (d, 1H, J = 9.1 Hz), 797 N4- (3,4-Dichlorophenyl)-5-fluoro-N2-[1-(3- 1H NMR (DMSO-d6): d 10.13 (s, 1H), 10.02 (s, 1H), 8.31 (d, 1H, J= + + − methoxypropyl)indazol-6-yl]-2,4-pyrimidinediamine 4.1 Hz), 8.06(d, 1H, J = 2.3 Hz), 7.95 (s, 1H), 7.87 (s, 1H), 7.74 (dd, 1H, J = 2.3and 8.8 Hz), 7.65 (d, 1H, J = 8.5 Hz), 7.54 (d, 1H, J = 8.8 Hz), 7.22(d, 1H, J = 8.5 Hz), 4.17 (t, 2H, 798 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 10.73 (s, 1H), 9.92 (s, 2H), 8.21 (d, 1H, J = 4.7 + + + [1-(3-methoxypropyl)indazol-6-yl]-2,4-pyrimidinediamine Hz), 7.92 (s, 1H),7.89 (s, 1H), 7.58 (d, 1H, J = 8.8 Hz), 7.29-7.24 (m, 3H), 6.85 (d, 1H,J = 8.5 Hz), 4.17 (t, 2H, J = 6.7 Hz), 3.14 (app qt, 2H, J = 6.4 Hz),3.13 (s, 3H), 1.92 (app 799 (S)-5-Fluoro-N2-[1-(3-methoxypropyl)indazol-6-yl]-N4- (2- 1H NMR (DMSO-d6): d 10.76 (s,1H), 10.11 (s, 2H), 8.23 (d, 1H, J = + + −methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- 4.7 Hz), 7.94 (s, 1H),7.86 (s, 1H), 7.62 (d, 1H, J = 8.5 Hz), 7.28-7.19 pyrimidinediamine (m,3H), 6.88 (d, 1H, J = 8.5 Hz), 4.64 (qt, 1H, J = 6.7 Hz), 4.17 (t, 2H, J= 6.7 Hz), 3.16 (app qt, 2H, J = 6.7 Hz 800 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2- (2-trifluoromethyl- 1H NMR(DMSO-d6): d 10.17 (s, 1H), 8.20 (d, 1H, J = 4.9 Hz), 7.85 (s, + + + +1H-benzimidazol-5-yl)-2,4-pyrimidinediamine 1H), 7.69 (d, 1H, J = 2.3Hz), 7.61 (d, 1H, J = 8.8 Hz), 7.59 (dd, 1H, J = 2.3 and 8.8 Hz), 7.39(dd, 1H, J = 2.0 and 8.8 Hz), 7.04 (d, 1H, J = 9.1 Hz), 3.76 (s, 3H).801 N4- (3,4-Dichlorophenyl)-5-fluoro-N2- (2-trifluoromethyl-1H- 1H NMR(DMSO-d6): d 9.84 (s, 1H), 9.70 (s, 1H), 8.19 (d, 1H, J = 4.1 + + + +benzimidazol-5-yl)-2,4-pyrimidinediamine Hz), 8.05 (d, 1H, J = 2.3 Hz),7.96 (s, 1H), 7.75 (dd, 1H, J = 2.3 and 8.8 Hz), 7.60 (d, 1H, J = 9.1Hz), 7.47-7.43 (m, 2H). 802 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 10.71 (s, 1H), 10.26 (s, 1H), 10.21 (s, 1H), + + − +(2-trifluoromethyl-1H-benzimidazol-5-yl)-2,4-pyrimidinediamine 8.22 (d,1H, J = 4.9 Hz), 7.88 (s, 1H), 7.61 (d, 1H, J = 8.8 Hz), 7.49 (dd, 1H, J= 2.3 and 8.8 Hz), 7.24 (s, 1H), 7.22 (s, 1H), 6.86 (d, 1H, J = 8.8 Hz),1.36 (s, 6H). 803 (S)-5-Fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)- 1H NMR (DMSO-d6): d 10.71(s, 1H), 10.27 (s, 1H), 10.22 (s, 1H), + + − N2-(2-trifluoromethyl-1H-benzimidazol-5-yl)-2,4- 8.22 (d, 1H, J = 4.9 Hz),7.93 (s, 1H), 7.62 (d, 1H, J = 8.8 Hz), 7.46 pyrimidinediamine (dd, 1H,J = 2.3 and 8.8 Hz), 7.24 (s, 1H), 7.21 (s, 1H), 6.89 (d, 1H, J = 8.8Hz), 4.66 (qt, 1H, J = 6.7 Hz), 1.40 (d, 804 N2-(3-Amino-1-methylindazol-5-yl)-N4- (3-chloro-4- 1H NMR (DMSO-d6): d10.13 (s, 1H), 9.94 (s, 1H), 8.17 (d, 1H, J = 4.9 + +methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine Hz), 7.76 (s, 1H), 7.75(d, 1H, J = 2.3 Hz), 7.61 (dd, 1H, J = 2.3 and 9.1 Hz), 7.44 (s, 2H),7.05 (d, 1H, J = 9.1 Hz), 3.80 (s, 3H), 3.79 (s, 3H). 805 N2-(3-Amino-1-methylindazol-5-yl)-N4- (3,4-dichlorophenyl)-5- 1H NMR(DMSO-d6): d 10.17 (s, 1H), 9.90 (s, 1H), 8.21 (d, 1H, J = +fluoro-2,4-pyrimidinediamine 4.7 Hz), 7.97 (d, 1H, J = 2.3 Hz), 7.90(dd, 1H, J = 2.3 and 8.8 Hz), 7.59 (d, 1H, J = 8.8 Hz), 7.47 (d, 1H, J =8.8 Hz), 7.38 (dd, 1H, J = 2.0 and 8.8 Hz), 4.41 (d, 2H, J = 6.7 Hz),3.88 806 N2- (3-Amino-1-methylindazol-5-yl)-N4- (2,2-dimethyl-3-oxo-4H-1H NMR (DMSO-d6): d 10.75 (s, 1H), 10.46 (s, 1H), 10.40 (s, 1H), + +benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.22 (d, 1H, J =4.9 Hz), 7.79 (s, 1H), 7.54 (dd, 1H, J = 2.3 an d8.8 Hz), 7.48 (d, 1H, J= 9.1 Hz), 7.28 (app br s, 1H), 7.22 (dd, 1H, J = 2.3 and 9.1 Hz), 6.54(d, 1H, J = 8.8 Hz), 3.84 (s, 807 (S)-N2-(3-Amino-1-methylindazol-5-yl)-5-fluoro-N4- (2-methyl- 1H NMR (DMSO-d6):d 10.76 (s, 1H), 10.38 (s, 1H), 10.28 (s, 1H), + +3-oxo-4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 8.20 (d, 1H, J =5.3 Hz), 7.80 (s, 1H), 7.53 (d, 1H, J = 9.1 Hz), 7.48 (d, 1H, J = 9.1Hz), 7.27 (s, 1H), 7.25 (s, 1H), 6.87 (d, 1H, J = 9.1 Hz), 4.63 (qt, 1H,J = 6.7 Hz), 3.83 (s, 3H), 1.3 808 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2- (2-methyl-3H- 1H NMR (DMSO-d6):d 9.53 (s, 1H), 9.40 (s, 1H), 8.14 (d, 1H, J = 3.8 + + − +benzimidazol-5-yl)-2,4-pyrimidinediamine Hz), 8.13 (s, 1H), 7.86 (d, 1H,J = 2.6 Hz), 7.72-7.67 (m, 2H), 7.59 (d, 1H, J = 8.8 Hz), 7.11 (d, 1H, J= 9.1 Hz), 3.83 (s, 3H), 2.72 (s, 3H). 809 N4-(3,4-Dichlorophenyl)-5-fluoro-N2- (2-methyl-3H- 1H NMR (DMSO-d6): d 9.93(s, 2H), 8.28 (d, 1H, J = 4.8 Hz), 8.12 (d, + + − +benzimidazol-5-yl)-2,4-pyrimidinediamine 1H, J = 2.6 Hz), 8.07 (s, 1H),7.81 (dd, 1H, J = 2.3 and 9.1 Hz), 7.66 (s, 2H), 7.56 (d, 1H, J = 8.8Hz), 2.75 (s, 3H). 810 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 10.70 (s, 1H), 9.56 (s, 1H), 9.40 (s, 1H), 8.21 + + − +(2-methyl-3H-benzimidazol-5-yl)-2,4-pyrimidinediamine (s, 1H), 8.12 (d,1H, J = 3.8 Hz), 7.79 (dd, 1H, J = 2.3 and 9.1 Hz), 7.55 (d, 1H, J = 8.8Hz), 7.52 (s, 1H), 7.31 (dd, 1H, J = 2.3 and 8.8 Hz), 6.88 (d, 1H, J =8.8 Hz), 2.72 (s, 3H), 1. 811 (S)-5-Fluoro-N2-(2-methyl-3H-benzimidazol-5-yl)-N4- (2- 1H NMR (DMSO-d6): d 10.69 (s,1H), 9.58 (s, 1H), 9.42 (s, 1H), 8.23 + + − +methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- (s, 1H), 8.12 (d, 1H, J =3.5 Hz), 7.74 (dd, 1H, J = 2.3 and 8.8 Hz), pyrimidinediamine 7.57 (d,1H, J = 9.1 Hz), 7.53 (d, 1H, J = 2.3 Hz), 7.29 (dd, 1H, J = 2.3 and 8.8Hz), 6.91 (d, 1H, J = 8.8 Hz), 4.64 812 N2-(1,3-Dimethylindazol-6-yl)-N4- (2,2-dimethyl-3-oxo-4H-5- 1H NMR(DMSO-d6): d 11.06 (s, 1H), 9.53 (s, 1H), 9.44 (s, 1H), 8.16 +pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine (d, 1H, J = 3.5Hz), 7.83 (s, 1H), 7.53 (d, 1H, J = 8.5 Hz), 7.45 (d, 1H, J = 8.8 Hz),7.30 (d, 1H, J = 8.5 Hz), 7.15 (dd, 1H, J = 2.3 and 8.8 Hz), 3.67 (s,3H), 2.33 (s, 3H), 1.36 (s, 6H 813 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 12.21 (s, 1H), 11.02 (s, 1H), 9.30 (s, 1H), 9.12 + N2-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine (s, 1H), 8.11 (d, 1H, J= 3.5 Hz), 7.90 (s, 1H), 7.69 (d, 1H, J = 8.5 Hz), 7.43 (d, 1H, J = 8.5Hz), 7.33 (d, 1H, J = 8.8 Hz), 7.19 (d, 1H, J = 8.8 Hz), 2.34 (s, 3H),1.36 (s, 6H). 814 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 11.10 (s, 1H), 9.22 (s, 1H), 9.19 (s, 1H), 8.12 + N2-[1-(3-methoxypropyl)indazol-5-yl]-2,4-pyrimidinediamine (d, 1H, J = 3.5Hz), 8.05 (s, 1H), 7.84 (s, 1H), 7.57 (d, 1H, J = 8.5 Hz), 7.50 (d, 1H,J = 8.8 Hz), 7.46 (d, 1H, J = 8.8 Hz), 7.35 (d, 1H, J = 8.8 Hz), 4.37(t, 2H, J = 6.4 Hz), 3.22 (t, 815 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-[3- (N- 1H NMR (DMSO-d6): d10.36 (s, 1H), 10.25 (s, 1H), 8.21 (d, 1H, J = +phthalimidopropyl)]indazol-5-yl]-2,4-pyrimidinediamine 4.9 Hz), 7.85 (s,1H), 7.79-7.75 (m, 5H), 7.67 (d, 1H, J = 2.3 Hz), 7.63 (d, 1H, J = 8.8Hz), 7.49 (dd, 1H, J = 2.3 and 8.8 Hz), 7.32 (dd, 1H, J = 1.8 and 9.1Hz), 7.03 (d, 1H, J = 8.8 Hz) 816 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-[3- (N- 1H NMR (DMSO-d6): d 10.24(s, 1H), 9.99 (s, 1H), 8.23 (d, 1H, J = 4.7 −phthalimidopropyl)]indazol-5-yl]-2,4-pyrimidinediamine Hz), 7.95 (d, 1H,J = 2.0 Hz), 7.87 (s, 1H), 7.80 (s, 1H), 7.78-7.73 (m, 4H), 7.64 (d, 1H,J = 9.1 Hz), 7.45 (d, 1H, J = 8.8 Hz), 7.36 (dd, 1H, J = 1.8 and 9.1Hz), 4.41 (t, 2H, J = 6.7 817 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 10.78 (s, 1H), 10.45 (s, 1H), 10.32 (s, 1H), + [1-[3-(N-phthalimidopropyl)]indazol-5-yl]-2,4-pyrimidinediamine 8.24 (d, 1H, J= 4.9 Hz), 7.88 (s, 1H), 7.87 (s, 1H), 7.84-7.77 (m, 4H), 7.65 (d, 1H, J= 8.8 Hz), 7.37 (dd, 1H, J = 1.8 and 9.1 Hz), 7.20 (d, 1H, J = 8.8 Hz),6.86 (d, 1H, J = 9.1 Hz), 4.4 818 (S)-5-Fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)- 1H NMR (DMSO-d6): d 10.80(s, 1H), 10.44 (s, 1H), 10.30 (s, 1H), + N2-[1-[3-(N-phthalimidopropyl)]indazol-5-yl]-2,4- 8.24 (d, 1H, J = 5.3 Hz), 7.89(s, 1H), 7.87 (s, 1H), 7.82-7.77 (m, 4H), pyrimidinediamine 7.67 (d, 1H,J = 8.8 Hz), 7.37 (dd, 1H, J = 1.8 and 9.1 Hz), 7.22 (dd, 1H, J = 1.8and 8.8 Hz), 7.18 (s, 1H), 6.89 (d 819 N2-[1-[3-(N-Acetylamino)propyl]indazol-5-yl]-N4- (3-chloro-4- 1H NMR (DMSO-d6): d10.22 (s, 1H), 10.05 (s, 1H), 8.21 (d, 1H, J = + +methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 4.9 Hz), 7.92 (s, 1H),7.90 (m, 1H), 7.86 (s, 1H), 7.75 (d, 1H, J = 2.3 Hz), 7.64 (d, 1H, J =9.1 Hz), 7.57 (dd, 1H, J = 2.3 and 8.8 Hz), 7.39 (dd, 1H, J = 1.8 and8.8 Hz), 7.09 (d, 1H, J 820 N2-[1-[3-(N-Acetylamino)propyl]indazol-5-yl]-N4- (3,4- 1H NMR (DMSO-d6): d 9.51(s, 1H), 9.23 (s, 1), 8.10 (d, 1H, J = 3.8 +dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine Hz), 8.04 (d, 1H, J = 2.3Hz), 7.95 (s, 1H), 7.82 (m, 2H), 7.74 (dd, 1H, J = 2.0 and 9.1 Hz), 7.51(d, 1H, J = 9.1 Hz), 7.44 (d, 1H, J = 9.1 Hz), 7.43 (dd, 1H, J = 1.8 and9.1 Hz), 4.30 ( 821 N2-[1-[3- (N-Acetylamino)propyl]indazol-5-yl]-N4-(2,2-dimethyl- 1H NMR (DMSO-d6): d 10.77 (s, 1H), 10.38 (s, 1H), 10.18(s, 1H), + 3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine8.21 (d, 1H, J = 4.9 Hz), 7.90 (s, 3H), 7.61 (d, 1H, J = 8.8 Hz), 7.36(dd, 1H, J = 2.0 and 9.1 Hz), 7.21 (d, 1H, J = 8.5 Hz), 7.18 (s, 1H),6.89 (d, 1H, J = 8.5 Hz), 4.36 (t, 2H, J = 7.0 Hz 822 N2-[1-[3-(N-Acetylamino)propyl]indazol-5-yl]-N4- (2,2-dimethyl- 1H NMR (DMSO-d6):d 11.05 (s, 1H), 9.18 (s, 1H), 9.15 (s, 1H), 8.07 + +3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4- (d, 1H), 3.5 Hz), 8.01(s, 1H), 7.80 (d, 1H, J = 6.3 Hz), 7.79 (s, 1H), pyrimidinediamine 7.52(d, 1H, J = 8.5 Hz), 7.48-7.40 (m, 2H), 7.31 (d, 1H, J = 8.5 Hz), 4.29(t, 2H, J = 7.0 Hz), 2.94 (qt, 2H, J = 823 N2-[1-(3-Aminopropyl)indazol-5-yl]-N4- (3-chloro-4- 1H NMR (DMSO-d6): d 10.25(s, 1H), 10.21 (s, 1H), 8.21 (d, 1H, J = +methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 4.8 Hz), 7.97 (br s, 2H),7.88 (s, 1H), 7.84-7.78 (m, 2H), 7.70 (d, 1H, J = 2.6 Hz), 9.08 (d, 1H,J = 9.1 Hz), 7.49 (dd, 1H, J = 2.6 and 8.8 Hz), 7.36 (dd, 1H, J = 1.8and 8.8 Hz), 7.06 (d 824 N2-[1- (3-Aminopropyl)indazol-5-yl]-N4-(3,4-dichlorophenyl)-5- 1H NMR (DMSO-d6): d 10.01 (s, 1H), 9.77 (s, 1H),8.24 (d, 1H, J = 3.1 + fluoro-2,4-pyrimidinediamine Hz), 8.06 (d, 1H, J= 2.6 Hz), 7.96 (s, 1H), 7.95 (s, 1H), 7.90-7.85 (m, 2H), 7.75 (d, 1H, J= 8.5 Hz), 7.67 (d, 1H, J = 8.8 Hz), 7.53 (d, 1H, J = 8.8 Hz), 7.47 (dd,1H, J = 2.0 and 9.1 825 N2-[1- (3-Aminopropyl)indazol-5-yl]-N4-(2,2-dimethyl-3-oxo-4H- 1H NMR (DMSO-d6): d 10.77 (s, 1H), 10.35 (s,2H), 8.20 (d, 1H, J = +benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 5.0 Hz), 7.94 (brs, 2H), 7.94 (s, 1H), 7.86 (s, 1H), 7.82-7.79 (m, 1H), 7.62 (d, 1H, J =9.1 Hz), 7.34 (dd, 1H, J = 1.8 and 9.1 Hz), 7.21 (br s, 1H), 7.15 (dd,1H, J = 1.8 and 8.8 Hz), 826 (S)-N2-[1-(3-Aminopropyl)indazol-5-yl]-5-fluoro-N4- (2-methyl- 1H NMR (DMSO-d6): d10.78 (s, 1H), 10.30 (s, 2H), 8.18 (d, 1H, J = +3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 4.9 Hz), 7.93(br s, 2H), 7.91 (s, 1H), 7.87 (s, 1H), 7.83-7.80 (m, 1H), 7.63 (d, 1H,J = 8.8 Hz), 7.36 (dd, 1H, J = 1.8 and 8.8 Hz), 7.21 (br s, 1H), 7.17(dd, 1H, J = 2.3 and 8.5 Hz), 827 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1- (3- 1H NMR (DMSO-d6): d 10.39(s, 1H), 10.03 (s, 1H), 8.20 (d, 1H, J = + −hydroxypropyl)indazol-5-yl]-2,4-pyrimidinediamine p- 5.3 Hz), 7.95 (s,1H), 7.80 (d, 1H, J = 1.8 Hz), 7.74 (d, 1H, J = 2.6 Toluenesulfonic AcidSalt Hz), 7.64 (d, 1H, J = 8.8 Hz), 7.54 (dd, 1H, J = 2.6 and 9.1 Hz),7.46 (d, 2H, J = 8.1 Hz), 7.38 (dd, 1H, J = 2.1 and 828 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1- (3- 1H NMR (DMSO-d6): d 10.63(s, 1H), 10.23 (s, 1H), 8.24 (d, 1H, J = + + −hydroxypropyl)indazol-5-yl]-2,4-pyrimidinediamine Bis p- 5.5 Hz), 7.97(s, 1H), 7.76 (d, 1H, J = 1.8 Hz), 7.72 (d, 1H, J = 2.4 Hz),Toluenesulfonic Acid Salt 7.66 (d, 1H, J = 9.1 Hz), 7.52 (dd, 1H, J =2.6 and 8.8 Hz), 7.47 (d, 4H, J = 8.1 Hz), 7.35 (dd, 1H, J = 1.8 and 829N4- (3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1- (3- 1H NMR (DMSO-d6): d10.38 (s, 1H), 10.02 (s, 1H), 8.19 (d, 1H, J = + + +hydroxypropyl)indazol-5-yl]-2,4-pyrimidinediamine 4.7 Hz), 7.95 (s, 1H),7.80 (s, 1H), 7.74 (s, 1H), 7.65-7.58 (m, 4H), Benzenesulfonic Acid Salt7.38 (d, 1H, J = 9.1 Hz), 7.29 (s, 3H), 7.07 (d, 1H, J = 8.8 Hz), 4.42(t, 2H, J = 6.7 Hz), 3.82 (s, 3H), 3.37 (t, 2H, 830 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1- (3- 1H NMR (DMSO-d6): d 10.29(s, 1H), 9.95 (s, 1H), 8.19 (d, 1H, J = 5.1 + + −hydroxypropyl)indazol-5-yl]-2,4-pyrimidinediamine Bis Hz), 7.94 (s, 1H),7.81 (d, 1H, J = 1.8 Hz), 7.75 (d, 1H, J = 2.6 Hz), Benzenesulfonic AcidSalt 7.65-7.53 (m, 7H), 7.39 (dd, 1H, J = 2.0 and 8.8 Hz), 7.31-7.26 (m,5H), 7.07 (d, 1H, J = 8.8 Hz), 4.42 (t, 2H, J 831 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1- (3- 1H NMR (DMSO-d6): d 10.36(s, 1H), 10.25 (s, 1H), 8.21 (d, 1H, J = + + −hydroxypropyl)indazol-5-yl]-2,4-pyrimidinediamine Hydrogen 5.3 Hz), 7.87(s, 1H), 7.77 (d, 1H, J = 1.5 Hz), 7.69 (d, 1H, J = 2.1 Hz), ChlorideSalt 7.57 (d, 1H, J = 9.1 Hz), 7.49 (dd, 1H, J = 2.3 and 8.8 Hz), 7.33(dd, 1H, J = 2.0 and 9.1 Hz), 7.03 (d, 1H, J = 832 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-[3- (N- 1H NMR (DMSO-d6): d10.60 (s, 1H), 10.52 (s, 1H), 8.30 (d, 1H, J = + + −methylsulfonylamino)propyl]indazol-5-yl]-2,4- 5.6 Hz), 7.95 (s, 1H),7.81 (d, 1H, J = 1.8 Hz), 7.73 (d, 1H, J = 2.3 Hz), pyrimidinediamine7.69 (d, 1H, J = 9.1 Hz), 7.52 (dd, 1H, J = 2.3 and 8.8 Hz), 7.37 (dd,1H, J = 2.0 and 8.8 Hz), 7.10 (br s, 1H), 7 833 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-[3- (N- 1H NMR (DMSO-d6): d 9.53 (s,1H), 9.25 (s, 1H), 8.11 (d, 1H, J = 3.8 + + −methylsulfonylamino)propyl]indazol-5-yl]-2,4- Hz), 8.04 (d, 1H, J = 2.3Hz), 7.97 (br s, 1H), 7.83 (s, 1H), 7.73 (d, 1H, pyrimidinediamine J =2.3 and 8.8 Hz), 7.53 (d, 1H, J = 8.8 Hz), 7.44 (d, 1H, J = 8.8 Hz),7.43 (dd, 1H, J = 2.3 and 8.8 Hz), 7.0 834 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 10.74 (s, 1H), 10.24 (s, 1H), , 9.98 (s, 1H), − + − [1-[3-(N-methylsulfonylamino)propyl]indazol-5-yl]-2,4- 8.21 (d, 1H, J = 4.3Hz), 7.93 (s, 1H), 7.90 (s, 1H), 7.61 (d, 1H, J = 8.8 pyrimidinediamineHz), 7.38 (dd, 1H, J = 1.8 and 9.1 Hz), 7.22 (dd, 1H, J = 1.8 and 8.8Hz), 7.17 (s, 1H), 7.09 (app t, 1H, J = 5.3 835 (S)-5-Fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)- 1H NMR (DMSO-d6): d 10.80(s, 1H), 10.42 (s, 1H), 10.25 (s, 1H), + + − N2-[1- (3-(N-methylsulfonylamino)propyl)indazol-5-yl]-2,4- 9.98 (s, 1H), 8.22 (d,1H, J = 4.9 Hz), 7.92 (s, 1H), 7.90 (d, 1H, J = 1.5 pyrimidinediamineHz), 7.64 (d, 1H, J = 8.8 Hz), 7.38 (dd, 1H, J = 2.0 and 9.1 Hz), 7.24-7.19 (m, 3H), 7.09 (t, 1H, J = 5.3 Hz), 6.91 836 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 11.11 (s, 1H), 9.25 (s, 1H), 9.24 (s, 1H), 8.11 + + −N2-[1-[3- (N-methylsulfonylamino)propyl]indazol-5-yl]-2,4- (d, 1H, J =3.0 Hz), 8.07 (s, 1H), 7.85 (s, 1H), 7.58 (d, 1H, J = 8.5 Hz),pyrimidinediamine 7.54 (d, 1H, J = 9.1 Hz), 7.48 (d, 1H, J = 9.1 Hz),7.36 (d, 1H, J = 8.5 Hz), 7.06 (t, 1H, J = 6.7 Hz), 4.39 (t, 837 N2-(3-Amino-1-methylindazol-5-yl)-N4- (2,2-dimethyl-3-oxo-4H- 1H NMR(DMSO-d6): d 11.17 (s, 1H), 10.22 (s, 1H), 10.13 (s, 1H), + +5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 8.25 (d, 1H, J =4.4 Hz), 7.92 (s, 1H), 7.58 (d, 1H, J = 9.1 Hz), 7.50 (d, 1H, J = 9.1Hz), 7.34 (d, 1H, J = 8.5 Hz), 3.86 (s, 3H), 1.39 (s, 3H). 838 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 11.22 (s, 1H), 10.22 (s, 1H), 10.09 (s, 1H), + + N2-[1-(3-hydroxypropyl)indazol-5-yl]-2,4-pyrimidinediamine 8.25 (d, 1H, J =4.4 Hz), 7.90 (s, 2H), 7.57 (d, 1H, J = 9.3 Hz), 7.41- 7.35 (m, 3H),4.40 (t, 2H, J = 6.7 Hz), 3.35 (t, 2H, J = 6.4 Hz), 1.93 (app q, 2H, J =6.7 Hz), 1.40 (s, 6H). 839 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 11.10 (s, 1H), 9.46 (s, 1H), 9.27 (s, 1H), 8.19 + + N2-[1-(3-methoxypropyl)indazol-6-yl]-2,4-pyrimidinediamine (d, 1H, J = 3.5Hz), 8.01 (s, 1H), 7.87 (s, 1H), 7.65 (d, 1H, J = 8.5 Hz), 7.54 (d, 1H,J = 8.8 Hz), 7.35 (d, 1H, J = 8.5 Hz), 7.29 (d, 1H, J = 8.8 Hz), 4.19(t, 2H, J = 6.7 Hz), 3.16 (t, 840 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-[3- (N- 1H NMR (DMSO-d6): d9.47 (br s, 1H), 9.28 (s, 1H), 9.17 (s, 1H), +trifluoromethylsulfonylamino)propyl]indazol-5-yl]-2,4- 8.07 (d, 1H, J =3.8 Hz), 8.04 (s, 1H), 7.84 (s, 1H), 7.79 (d, 1H, J = 2.6pyrimidinediamine Hz), 7.64 (dd, 1H, J = 2.3 and 9.1 Hz), 7.52 (d, 1H, J= 8.8 Hz), 7.49 (d, 1H, J = 9.1 Hz), 7.07 (d, 1H, J = 8.8 H 841 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-[3- (N- 1H NMR (DMSO-d6): d 10.48(s, 1H), 10.28 (s, 1H), 9.55 (t, 1H, J = +trifluoromethylsulfonylamino)propyl]indazol-5-yl]-2,4- 5.2 Hz), 8.32 (d,1H, J = 4.9 Hz), 8.00 (d, 1H, J = 2.0 Hz), 7.98 (s, 1H),pyrimidinediamine 7.85-7.81 (m, 1H), 7.70-7.65 (m, 2H), 7.52 (d, 1H, J =8.8 Hz), 7.42 (dd, 1H, J = 2.0 and 9.1 Hz), 4.45 (t, 2H, 842 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 10.63 (s, 1H), 9.46 (brs, 1H), 9.28 (s, 1H), + [1-[3-(N-trifluoromethylsulfonylamino)propyl]indazol-5-yl]-2,4- 9.06 (s, 1H),8.12 (s, 1H), 8.05 (d, 1H, J = 3.8 Hz), 7.80 (s, 1H), 7.47pyrimidinediamine (app d, 2H, J = 9.1 Hz), 7.29 (dd, 1H, J = 2.0 and 8.8Hz), 7.20 (d, 1H, J = 2.0 Hz), 6.89 (d, 1H, J = 8.8 Hz), 4.37 843(S)-5-Fluoro-N4- (2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)- 1H NMR(DMSO-d6): d 10.74 (s, 1H), 9.88 (s, 1H), 9.68 (s, 1H), 9.49 + N2-[1-[3-(N-trifluoromethylsulfonylamino)propyl]indazol-5-yl]- (t, 1H, J = 6.7Hz), 8.13 (d, 1H, J = 4.7 Hz), 8.01 (s, 1H), 7.87 (s, 1H),2,4-pyrimidinediamine 7.56 (d, 1H, J = 9.1 Hz), 7.43 (d, 1H, J = 9.1Hz), 7.26 (d, 1H, J = 8.5 Hz), 7.21 (s, 1H), 6.90 (d, 1H, J = 8.5 844N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 11.10 (s, 1H), 9.46 (br s, 1H), 9.23 (s, 1H), − N2-[1-[3-(N-trifluoromethylsulfonylamino)propyl]indazol-5-yl]- 9.19 (s, 1H), 8.11(dd, 1H, J = 0.9 and 3.5 Hz), 8.07 (s, 1H), 7.86 (s,2,4-pyrimidinediamine 1H), 7.59 (d, 1H, J = 8.5 Hz), 7.53 (d, 1H, J =9.1 Hz), 7.49 (d, 1H, J = 8.8 Hz), 7.35 (d, 1H, J = 8.5 Hz), 4.39 (t,845 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 11.11 (s, 1H), 9.68 (s, 1H), 9.42 (s, 1H), 8.20 + + + N2-(2-methyl-3H-benzimidazol-5-yl)-2,4-pyrimidinediamine (d, 1H, J = 3.5Hz), 8.13 (s, 1H), 7.73 (dd, 1H, J = 1.8 and 9.1 Hz), 7.63 (d, 1H, J =8.5 Hz), 7.57 (d, 1H, J = 9.1 Hz), 7.39 (d, 1H, J = 8.5 Hz), 2.73 (s,3H), 1.42 (s, 6H). 846 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 13.56 (br s 1H), 11.07 (s, 1H), 9.43 (s, 1H), + + + N2-(2-trifluoromethyl-1H-benzimidazol-5-yl)-2,4- 9.20 (s, 1H), 8.16 (d, 1H,J = 3.5 Hz), 8.13 (s, 1H), 7.73 (dd, 1H, J = pyrimidinediamine 1.8 and9.1 Hz), 7.61 (d, 1H, J = 8.5 Hz), 7.55 (d, 1H, J = 9.1 Hz), 7.36 (d,1H, J = 8.5 Hz), 1.42 (s, 6H). 847 N4- (3-Chloro-4-methoxyphenyl)-N2-[1-(3- 1H NMR (DMSO-d6): d 9.27 (s, 1H), 9.16 (s, 1H), 8.07 (d, 1H, J =3.5 + (diethylphosphonamido)propyl]indazol-5-yl]-5-fluoro-2,4- Hz), 8.03(s, 1H), 7.82 (s, 1H), 7.79 (d, 1H, J = 2.3 Hz), 7.65 (dd, 1H, J =pyrimidinediamine 2.3 and 8.5 Hz), 7.53 (d, 1H, J = 8.5 Hz), 7.47 (d,1H, J = 9.1 Hz), 7.08 (d, 1H, J = 9.1 Hz), 4.91 (dt, 1H, 848 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1- (3- 1H NMR (DMSO-d6): d 10.42(s, 1H), 10.29 (s, 1H), 8.26 (d, 1H, J = +pivalamidopropyl)indazol-5-yl]-2,4-pyrimidinediamine 4.9 Hz), 7.93 (s,1H), 7.83 (s, 1H), 7.74 (s, 1H), 7.62 (d, 1H, J = 8.8 Hz), 7.55-7.47 (m,2H), 7.39 (d, 1H, J = 9.1 Hz), 7.09 (d, 1H, J = 8.8 Hz), 4.35 (t, 2H, J= 7.0 Hz), 3.82 (s, 3H), 849 N4- (3,4-Dichlorophenyl)-5-fluoro-N2-[1-(3- 1H NMR (DMSO-d6): d 9.55 (s, 1H), 9.28 (s, 1H), 8.15 (dd, 1H, J =1.2 + pivalamidopropyl)indazol-5-yl]-2,4-pyrimidinediamine and 3.7 Hz),8.09 (d, 1H, J = 1.5 Hz), 8.00 (s, 1H), 7.87 (s, 1H), 7.79 (dd, 1H, J =1.8 and 9.1 Hz), 7.54-7.44 (m, 4H), 4.33 (t, 2H, J = 6.7 Hz), 3.04 (qt,2H, J = 6.4 Hz), 1.94 (app q 850 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 10.74 (s, 1H), 10.21 (s, 1H), 9.89 (s, 1H), 8.18 + [1-(3-pivalamidopropyl)indazol-5-yl]-2,4-pyrimidinediamine (d, 1H, J = 4.4Hz), 7.93 (s, 1H), 7.88 (s, 1H), 7.56 (d, 1H, J = 8.5 Hz), 7.46 (t, 1H,J = 5.6 Hz), 7.37 (d, 1H, J = 9.1 Hz), 7.23 (d, 1H, J = 9.1 Hz), 7.17(s, 1H), 6.88 (d, 1H, J = 8. 851 5-Fluoro- (S)-N4-(2-methyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2- 1H NMR (DMSO-d6): d 10.80(s, 1H), 10.42 (s, 1H), 10.28 (s, 1H), + [1-(3-pivalamidopropyl)indazol-5-yl]-2,4-pyrimidinediamine 8.22 (d, 1H, J =4.4 Hz), 7.90 (s, 2H), 7.59 (d, 1H, J = 8.8 Hz), 7.47 (m, 1H), 7.38 (d,1H, J = 8.8 Hz), 7.22 (app d, 2H, J = 8.8 Hz), 6.91 (d, 1H, J = 8.8 Hz),4.64 (qt, 1H, J = 6.7 Hz), 4 852 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 11.10 (s, 1H), 9.22 (s, 1H), 9.18 (s, 1H), 8.12 + N2-[1-(3-pivalamidopropyl)indazol-5-yl]-2,4-pyrimidinediamine (d, 1H, J = 3.5Hz), 7.84 (s, 1H), 7.82 (s, 1H), 7.59 (d, 1H, J = 8.8 Hz), 7.48-7.43 (m,3H), 7.36 (d, 1H, J = 8.5 Hz), 4.32 (t, 2H, J = 6.7 Hz), 3.02 (qt, 2H, J= 6.7 Hz), 1.92 (app q, 2 853 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-[3- (N- 1H NMR (DMSO-d6): d9.28 (s, 1H), 9.17 (s, 1H), 8.07 (d, 1H, J = 3.5 + +succinimidopropyl)]indazol-5-yl]-2,4-pyrimidinediamine Hz), 7.82 (s,1H), 7.78 (d, 1H, J = 2.0 Hz), 7.66 (dd, 1H, J = 2.0 and 8.5 Hz), 7.52(d, 1H, J = 9.1 Hz), 7.46 (d, 1H, J = 9.1 Hz), 7.09 (d, 1H, J = 8.5 Hz),4.33 (t, 2H, J = 6.3 Hz), 3. 854 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-[3- (N- 1H NMR (DMSO-d6): d 9.55 (s,1H), 9.28 (s, 1H), 8.16 (d, 1H, J = 3.5 + −succinimidopropyl)]indazol-5-yl]-2,4-pyrimidinediamine Hz), 8.08 (d, 1H,J = 2.3 Hz), 8.01 (s, 1H), 7.88 (s, 1H), 7.80 (dd, 1H, J = 2.3 and 8.8Hz), 7.56 (d, 1H, J = 8.8 Hz), 7.51-7.46 (m, 2H), 4.35 (t, 2H, J = 6.7Hz), 3.40 (t, 2H, J = 7.0 855 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 10.73 (s, 1H), 10.38 (s, 1H), 10.25 (s, 1H), + + [1-[3-(N-succinimidopropyl)]indazol-5-yl]-2,4-pyrimidinediamine 8.18 (d, 1H, J= 3.9 Hz), 7.85 (s, 1H), 7.83 (s, 1H), 7.56 (d, 1H, J = 9.1 Hz), 7.32(d, 1H, J = 8.8 Hz), 7.14 (d, 2H, J = 9.1 Hz), 6.84 (d, 1H, J = 8.8 Hz),4.30 (t, 2H, J = 7.0 Hz), 3.34 (t 856 (S)-5-Fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)- 1H NMR (DMSO-d6): d 10.82(s, 1H), 10.52 (s, 1H), 10.42 (s, 1H), + + N2-[1-[3-(N-succinimidopropyl)]indazol-5-yl]-2,4- 8.24 (d, 1H, J = 4.9 Hz), 7.92(s, 1H), 7.87 (s, 1H), 7.63 (d, 1H, J = 8.8 pyrimidinediamine Hz), 7.37(dd, 1H, J = 1.0 and 8.8 Hz), 7.20 (d, 2H, J = 8.8 Hz), 6.91 (d, 1H, J =9.1 Hz), 4.65 (qt, 1H, J = 6.7 Hz 857 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 11.10 (s, 1H), 9.23 (s, 1H), 9.19 (s, 1H), 8.12 + +N2-[1-[3- (N-succinimidopropyl)]indazol-5-yl]-2,4- (d, 1H, J = 3.5 Hz),8.06 (s, 1H), 7.57 (d, 1H, J = 8.8 Hz), 7.53-7.46 pyrimidinediamine (m,2H), 7.36 (d, 1H, J = 8.8 Hz), 4.33 (t, 2H, J = 7.0 Hz), 3.39 (t, 2H, J= 6.7 Hz), 2.54 (s, 2H), 2.48 (s, 2H), 2 858 N4-(3-Chloro-4-methoxyphenyl)-N2-[1-[3- (2,6- 1H NMR (DMSO-d6): d 10.26 (s,1H), 10.08 (s, 1H), 8.22 (d, 1H, J = + +dioxopiperidino]propyl)indazol-5-yl]-5-fluoro-2,4- 4.3 Hz), 7.92 (s,1H), 7.85 (s, 1H), 7.74 (d, 1H, J = 2.0 Hz), 7.62 (d, 1H,pyrimidinediamine J = 8.8 Hz), 7.57 (dd, 1H, J = 2.3 and 8.8 Hz), 7.39(dd, 1H, J = 2.0 and 8.3 Hz), 7.09 (d, 1H, J = 8.8 Hz), 4.35 859 N4-(3,4-Dichlorophenyl)-N2-[1-[3- (2,6- 1H NMR (DMSO-d6): d 10.05 (s, 1H),9.77 (s, 1h), 8.23 (d, 1H, J = 5.1 + +dioxopiperidino)propyl]indazol-5-yl]-5-fluoro-2,4- Hz), 8.03 (s, 1H),7.92 (s, 1H), 7.91 (s, 1H), 7.73 (d, 1H, J = 8.8 Hz), pyrimidinediamine7.61 (d, 1H, J = 8.8 Hz), 7.51 (d, 1H, J = 8.8 Hz), 7.44 (d, 1H, J = 8.8Hz), 4.35 (t, 2H, J = 6.7 Hz), 3.67 (t, 2 860 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[1-[3- 1H NMR (DMSO-d6):d 10.76 (s, 1H), 10.34 (s, 1H), 10.16 (s, 1H), + +(2,6-dioxopiperidino]propyl)indazol-5-yl]-5-fluoro-2,4- 8.21 (d, 1H, J =4.3 Hz), 7.89 (s, 2H), 7.59 (d, 1H, J = 8.5 Hz), 7.37 pyrimidinediamine(dd, 1H, J = 1.5 and 8.5 Hz), 7.21 (d, 1H, J = 8.8 Hz), 7.19 (s, 1H),6.88 (d, 1H, J = 8.8 Hz), 4.35 (t, 2H, J = 7.0 Hz 861 (S)-N2-[1-[3-(2,6-Dioxopiperidino]propyl)indazol-5-yl]-5-fluoro- 1H NMR (DMSO-d6): d10.78 (s, 1H), 10.49 (s, 1H), 10.44 (s, 1H), + + N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- 8.21 (d, 1H, J = 4.9Hz), 7.85 (s, 1H), 7.82 (s, 1H), 7.56 (d, 1H, J = 8.8 pyrimidinediamineHz), 7.31 (d, 1H, J = 8.8 Hz), 7.17 (s, 1H), 7.16 (d, 1H, J = 8.8 Hz),6.86 (d, 1H, J = 8.8 Hz), 4.59 (qt, 1H, J = 862 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-[1-[3- 1H NMR(DMSO-d6): d 11.10 (s, 1H), 9.22 (s, 1H), 9.18 (s, 1H), 8.12 + +(2,6-dioxopiperidino]propyl)indazol-5-yl]-5-fluoro-2,4- (d, 1H, J = 3.2Hz), 8.05 (s, 1H), 7.84 (s, 1H), 7.58 (d, 1H, J = 8.2 Hz),pyrimidinediamine 7.48 (s, 2H), 7.36 (d, 1H, J = 8.2 Hz), 4.32 (t, 2H, J= 7.3 Hz), 3.66 (t, 2H, J = 7.3 Hz), 2.45 (t, 2H, J = 7.3 863 N4-(3,4-Dichlorophenyl)-5-fluoro-N2- (2-trifluoromethyl-1H- 1H NMR(DMSO-d6): d 10.33 (s, 1H), 10.23 (s, 1H), 8.32 (d, 1H, J = + +benzimidazol-5-yl)-2,4-pyrimidinediamine Hydrogen Chloride 4.7 Hz), 8.03(d, 1H, J = 2.0 Hz), 7.90 (s, 1H), 7.74 (d, 1H, J = 2.0 Hz), Salt 7.69(d, 1H, J = 8.8 Hz), 7.51 (d, 1H, J = 8.8 Hz), 7.45 (dd, 1H, J = 2.0 and8.8 Hz). 864 N4- (3,4-Dichlorophenyl)-5-fluoro-N2-(2-trifluoromethyl-1H- 1H NMR (DMSO-d6): d 10.11 (s, 1H), 9.92 (s, 1H),8.27 (d, 1H, J = 4.4 − + benzimidazol-5-yl)-2,4-pyrimidinediamineEthanesulfonic Acid Hz), 8.06 (d, 1H, J = 2.0 Hz), 7.94 (s, 1H), 7.76(d, 1H, J = 2.0 Hz), Salt 7.67 (d, 1H, J = 8.8 Hz), 7.51 (d, 1H, J = 8.8Hz), 7.41 (dd, 1H, J = 2.0 and 8.8 Hz), 2.42 (qt, 2H, J = 7.3 Hz), 1 865N4- (3,4-Dichlorophenyl)-5-fluoro-N2- (2-trifluoromethyl-1H- 1H NMR(DMSO-d6): d 10.25 (s, 1H), 10.04 (s, 1H), 8.29 (d, 1H, J = − +benzimidazol-5-yl)-2,4-pyrimidinediamine Benzenesulfonic 4.4 Hz), 8.03(s, 1H), 7.91 (s, 1H), 7.73-7.26 (m, 2H), 7.58-7.43 (m, Acid Salt 4H),7.29-7.27 (m, 3H). 866 N4- (3,4-Dichlorophenyl)-5-fluoro-N2-(2-trifluoromethyl-1H- 1H NMR (DMSO-d6): d 10.30 (s, 1H), 10.08 (s, 1H),8.30 (d, 1H, J = − + benzimidazol-5-yl)-2,4-pyrimidinediaminep-Toluenesulfonic 4.7 Hz), 8.03 (d, 1H, J = 2.0 Hz), 7.90 (s, 1H), 7.71(d, 2H, J = 8.8 Hz), Acid Salt 7.51 (d, 1H, J = 8.8 Hz), 7.47-7.43 (m,3H), 7.10 (d, 2H, J = 8.8 Hz), 2.26 (s, 3H). 867 N4-(3,4-Dichlorophenyl)-5-fluoro-N2- (2-methyl-3H- 1H NMR (DMSO-d6): d 9.77(s, 1H), 9.74 (s, 1H), 8.25 (d, 1H, J = 3.8 + +benzimidazol-5-yl)-2,4-pyrimidinediamine Benzenesulfonic Hz), 8.14 (d,1H, J = 2.3 Hz), 8.12 (s, 1H), 7.81 (dd, 1H, J = 2.3 and Acid Salt 8.8Hz), 7.66 (d, 2H, J = 9.1 Hz), 7.59-7.52 (m, 3H), 7.33-7.27 (m, 3H),2.74 (s, 3H). 868 N4- (3,4-Dichlorophenyl)-5-fluoro-N2- (2-methyl-3H- 1HNMR (DMSO-d6): d 9.78 (s, 1H), 9.74 (s, 1H), 8.25 (d, 1H, J = 3.8 + +benzimidazol-5-yl)-2,4-pyrimidinediamine p-Toluenesulfonic Hz), 8.14 (d,1H, J = 2.3 Hz), 8.12 (s, 1H), 7.81 (dd, 1H, J = 2.3 and Acid Salt 8.8Hz), 7.66 (d, 2H, J = 9.1 Hz), 7.54 (d, 1H, J = 8.8 Hz), 7.46 (d, 2H, J= 8.2 Hz), 7.10 (d, 2H, J = 8.2 Hz), 2.7 869 N4-(3,4-Dichlorophenyl)-5-fluoro-N2- (2-methyl-3H- 1H NMR (DMSO-d6): d 9.93(s, 2H), 8.28 (d, 1H, J = 3.8 Hz), 8.12 (d, + +benzimidazol-5-yl)-2,4-pyrimidinediamine Hydrogen Chloride 1H, J = 2.3Hz), 8.07 (s, 1H), 7.81 (dd, 1H, J = 1.8 and 8.8 Hz), 7.66 Salt (d, 2H,J = 8.8 Hz), 7.56 (d, 1H, J = 8.8 Hz), 2.75 (s, 3H). 870 N4-(3,4-Dichlorophenyl)-5-fluoro-N2- (2-methyl-3H- 1H NMR (DMSO-d6): d 9.75(s, 2H), 9.72 (s, 1H), 8.24 (d, 1H, J = 3.8 + +benzimidazol-5-yl)-2,4-pyrimidinediamine Ethanesulfonic Acid Hz), 8.14(d, 1H, J = 2.0 Hz), 8.12 (s, 1H), 7.82 (d, 1H, J = 8.8 Hz), Salt 7.66(d, 2H, J = 8.5 Hz), 7.53 (d, 1H, J = 8.8 Hz), 2.74 (s, 3H), 2.40 (qt,2H, J = 7.3 Hz), 1.05 (t, 3H, J = 7.3 H 871 N4-(3-Chloro-4-methoxyphenyl)-N2-[1- (3- 1H NMR (DMSO-d6): d 10.37 (s, 1H),10.23 (s, 1H), 8.25 (d, 1H, J = + +ethoxypropyl)indazol-5-yl]-5-fluoro-2,4-pyrimidinediamine 5.3 Hz), 7.92(s, 1H), 7.83 (s, 1H), 7.74 (d, 1H, J = 2.6 Hz), 7.59 (d, H, J = 8.8Hz), 7.53 (dd, 1H, J = 2.3 and 8.5 Hz), 7.38 (dd, 1H, J = 1.8 and 8.8Hz), 7.09 (d, 1H, J = 9.1 Hz), 4.40 872 N4- (3,4-Dichlorophenyl)-N2-[1-(3-ethoxypropyl)indazol-5-yl]-5- 1H NMR (DMSO-d6): d 10.27 (s, 1H),10.02 (s, 1H), 8.28 (d, 1H, J = + fluoro-2,4-pyrimidinediamine 4.7 Hz),8.02 (d, 1H, J = 2.3 Hz), 7.95 (s, 1H), 7.87 (s, 1H), 7.68 (d, 1H, J =8.8 Hz), 7.60 (d, 1H, J = 8.8 Hz), 7.51 (d, 1H, J = 8.8 Hz), 7.42 (dd,1H, J = 2.3 and 8.8 Hz), 4.41 (t, 2H, 873 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2-[1- (3- 1H NMR(DMSO-d6): d 10.76 (s, 1H), 10.36 (s, 1H), 10.19 (s, 1H), + +ethoxypropyl)indazol-5-yl]-5-fluoro-2,4-pyrimidinediamine 8.22 (d, 1H, J= 5.3 Hz), 7.90 (s, 2H), 7.55 (d, 1H, J = 9.1 Hz), 7.37 (dd, 1H, J = 1.8and 8.8 Hz), 7.20 (d, 1H, J = 8.8 Hz), 7.18 (s, 1H), 6.87 (d, 1H, J =8.8 Hz), 4.39 (t, 2H, J = 6.7 Hz 874 (S)-N2-[1-(3-Ethoxypropyl)indazol-5-yl]-5-fluoro-N4- (2-methyl- 1H NMR (DMSO-d6):d 10.79 (s, 1H), 10.40 (s, 1H), 10.24 (s, 1H), + +3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 8.22 (d, 1H, J =5.3 Hz), 7.90 (d, 1H, J = 1.8 Hz), 7.88 (s, 1H), 7.57 (d, 1H, J = 9.1Hz), 7.37 (dd, 1H, J = 1.8 and 9.1 Hz), 7.22 (dd, 2H, J = 1.8 and 8.5Hz), 6.89 (d, 1H, J = 8.5 Hz), 4. 875 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-[1- (3- 1H NMR(DMSO-d6): d 11.10 (s, 1H), 9.22 (s, 1H), 9.19 (s, 1H), 8.11 + +ethoxypropyl)indazol-5-yl]-5-fluoro-2,4-pyrimidinediamine (d, 1H, J =3.5 Hz), 8.05 (s, 1H), 7.84 (s, 1H), 7.58 (d, 1H, J = 8.5 Hz), 7.42 (d,2H, J = 8.8 Hz), 7.35 (d, 1H, J = 8.5 Hz), 4.37 (t, 2H, J = 6.7 Hz),3.32 (qt, 2H, J = 7.0 Hz), 3.28 (t 876 N4-(2-Chloro-3-methoxypyrid-6-yl)-5-fluoro-N2- (3,4,5- 1H NMR (DMSO-d6): d10.32 (s, 1H), 9.63 (s, 1H), 8.19 (d, 1H, J = 4.1 + +trimethoxyphenyl)-2,4-pyrimidinediamine Hz), 8.06 (d, 1H, J = 8.5 Hz),7.52 (d, 1H, J = 8.5 Hz), 6.91 (s, 2H), 3.88 (s, 3H), 3.64 (s, 6H), 3.61(s, 3H). 877 N4- (2-Chloro-3-methoxypyrid-6-yl)-N2-(3,4-dimethoxyphenyl)- 1H NMR (DMSO-d6): d 9.84 (s, 1H), 9.23 (s, 1H),8.15 (d, 1H, J = 8.8 + 5-fluoro-2,4-pyrimidinediamine Hz), 8.14 (d, 1H,J = 3.5 Hz), 7.55 (d, 1H, J = 9.1 Hz), 6.90 (d, 1H, J = 2.3 Hz), 6.08(d, 2H, J = 2.3 Hz), 3.88 (s, 3H), 3.65 (s, 3H). 878 N2-(3-Chloro-4-methoxyphenyl)-N4- (2-chloro-3-methoxypyrid- 1H NMR(DMSO-d6): d 9.83 (s, 1H), 9.26 (s, 1H), 8.14 (d, 1H, J = 3.5 −6-yl)-5-fluoro-2,4-pyrimidinediamine Hz), 8.01 (d, 1H, J = 9.1 Hz), 7.80(d, 1H, J = 2.6 Hz), 7.59 (d, 1H, J = 9.1 Hz), 7.43 (dd, 1H, J = 2.6 and9.1 Hz), 7.03 (d, 1H, J = 9.1 Hz), 3.88 (s, 3H), 3.78 (s, 3H). 879 N4-(2-Chloro-3-methoxypyrid-6-yl)-N2- (3,5-dimethylphenyl)-5- 1H NMR(DMSO-d6): d 9.79 (s, 1H), 9.15 (s, 1H), 8.13 (d, 1H, J = 3.5 + +fluoro-2,4-pyrimidinediamine Hz), 8.08 (dd, 1H, J = 2.3 and 8.8 Hz),7.57 (d, 1H, J = 8.8 Hz), 7.22 (s, 2H), 6.53 (s, 1H), 3.82 (s, 3H), 2.19(s, 6H). H+). 880 N4- (2-Chloro-3-methoxypyrid-6-yl)-5-fluoro-N2-[3- (N-1H NMR (DMSO-d6): d 9.84 (s, 1H), 9.32 (s, 1H), 8.14 (d, 1H, J = 3.5 + +methylamino)carbonylmethyleneoxyphenyl]-2,4- Hz), 8.12 (d, 1H, J = 8.8Hz), 7.96 (qt, 1H, J = 4.7 Hz), 7.60 (d, 1H, J = pyrimidinediamine 8.8Hz), 7.37 (app s, 1H), 7.23 (d, 1H, J = 8.2 Hz), 7.13 (t, 1H, J = 8.2Hz), 6.48 (dd, 1H, J = 2.3 and 8.2 Hz 881 2-Chloro-N4-(2-chloro-3-methoxypyrid-6-yl)-5-fluoro-4- 1H NMR (DMSO-d6): d 8.33 (d,1H, J = 8.8 Hz), 8.12 (d, 1H, J = 2.3 pyrimidineamine Hz), 7.65 (br s,1H), 7.38 (d, 1H, J = 8.8 Hz), 3.94 (s, 3H). 882 N4-(2-Chloro-3-methoxypyrid-6-yl)-5-fluoro-N2- (indazol-6-yl)- LCMS: ret.time: 10.99 min.; purity: 93%; MS (m/e): 386 (MH⁺). +2,4-pyrimidinediamine 883 N4-(2-Chloro-3-methoxypyrid-6-yl)-5-fluoro-N2- (2- LCMS: ret. time: 11.74min.; purity: 97%; MS (m/e): 454 (MH⁺). +trifluoromethyl-1H-benzimidazol-5-yl)-2,4-pyrimidinediamine 884 N4-(2-Chloro-3-methoxypyrid-6-yl)-5-fluoro-N2- (2-methyl-3H- LCMS: ret.time: 7.71 min.; purity: 93%; MS (m/e): 400 (MH⁺). +benzimidazol-5-yl)-2,4-pyrimidinediamine 885 N4-(2-Chloro-3-methoxypyrid-6-yl)-5-fluoro-N2- (1- LCMS: ret. time: 12.20min.; purity: 93%; MS (m/e): 400 (MH⁺). +methylindazol-6-yl)-2,4-pyrimidinediamine 886 N4-(2-Chloro-3-methoxypyrid-6-yl)-5-fluoro-N2- (1- LCMS: ret. time: 10.79min.; purity: 94%; MS (m/e): 400 (MH⁺). −methylindazol-5-yl)-2,4-pyrimidinediamine 887 N4-(2-Chloro-3-methoxypyrid-6-yl)-5-fluoro-N2- (1-ethylindazol- LCMS: ret.time: 12.97 min.; purity: 95%; MS (m/e): 414 (MH⁺). +6-yl)-2,4-pyrimidinediamine 888 N4-(2-Chloro-3-methoxypyrid-6-yl)-5-fluoro-N2- (1- LCMS: ret. time: 13.86min.; purity: 92%; MS (m/e): 428 (MH⁺). +isopropylindazol-6-yl)-2,4-pyrimidinediamine 889 N4-(2-Chloro-3-methoxypyrid-6-yl)-N2- (2,2-dimethyl-3-oxo-4H- LCMS: ret.time: 11.84 min.; purity: 94%; MS (m/e): 445 (MH⁺). +benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 890 N2-[1-[3-(N-Acetylamino)propyl]indazol-5-yl]-N4- (2-chloro-3- LCMS: ret. time:9.42 min.; purity: 95%; MS (m/e): 485 (MH⁺). +methoxypyrid-6-yl)-5-fluoro-2,4-pyrimidinediamine 891 N4-(2-Chloro-3-methoxypyrid-6-yl)-N2-[1-[3- (N- LCMS: ret. time: 10.30min.; purity: 95%; MS (m/e): 511 (MH⁺). +cyclopropanecarbonylamino)propyl]indazol-5-yl]-5-fluoro-2,4-pyrimidinediamine 892 N4- (2-Chloro-3-methoxypyrid-6-yl)-5-fluoro-N2-[1-(3- LCMS: ret. time: 11.73 min.; purity: 99%; MS (m/e): 527 (MH⁺). +pivalamidopropyl)indazol-5-yl]-2,4-pyrimidinediamine 893 N4-(2-Chloro-3-methoxypyrid-6-yl)-5-fluoro-N2-[1-[3- (N- LCMS: ret. time:10.71 min.; purity: 97%; MS (m/e): 514 (MH⁺). +isobutyrylamino)propyl]indazol-5-yl]-2,4-pyrimidinediamine 894 N4-(3,4-Dichlorophenyl)-N2- (1,2-dimethylbenzimidazol-5-yl)-5- LCMS: ret.time: 9.44 min.; purity: 100%; MS (m/e): 418 (MH⁺). +fluoro-2,4-pyrimidinediamine 895 N4- (3-Chloro-4-methoxyphenyl)-N2-(1,2- LCMS: ret. time: 7.66 min.; purity: 96%; MS (m/e): 413 (MH⁺). +dimethylbenzimidazol-5-yl)-5-fluoro-2,4-pyrimidinediamine 896 N2-(1,2-Dimethylbenzimidazol-5-yl)-N4- (2,2-dimethyl-3-oxo- LCMS: ret.time: 7.09 min.; purity: 99%; MS (m/e): 448 (MH⁺). + +4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 897 (S)-N2-(1,2-Dimethylbenzimidazol-5-yl)-5-fluoro-N4- (2-methyl- LCMS: ret. time:6.52 min.; purity: 97%; MS (m/e): 434 (MH⁺). + + +3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 898 N2-(1,2-Dimethylbenzimidazol-5-yl)-N4- (2,2-dimethyl-3-oxo- LCMS: ret.time: 7.85 min.; purity: 91%; MS (m/e): 449 (MH⁺). + + +4H-5-pyrid[1,4]oxazin-6-yl)-5-Fluoro-2,4-pyrimidinediamine 899 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1- (2-hydroxyethyl)-2- LCMS: ret.time: 8.77 min.; purity: 97%; MS (m/e): 448 (MH⁺). + +methylbenzimidazol-5-yl)-2,4-pyrimidinediamine 900 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1- (2- LCMS: ret. time: 7.06min.; purity: 93%; MS (m/e): 443 (MH⁺). +hydroxyethyl)-2-methylbenzimidazol-5-yl)-2,4- pyrimidinediamine 901 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- LCMS: ret.time: 6.50 min.; purity: 97%; MS (m/e): 478 (MH⁺). + + [1-(2-hydroxyethyl)-2-methylbenzimidazol-5-yl)-2,4- pyrimidinediamine 902(S)-5-Fluoro-N2-[1- (2-hydroxyethyl)-2-methylbenzimidazol-5- LCMS: ret.time: 5.99 min.; purity: 94%; MS (m/e): 464 (MH⁺). + + yl)-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- pyrimidinediamine 903N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- LCMS: ret.time: 6.89 min.; purity: 97%; MS (m/e): 479 (MH⁺). + + N2-[1-(2-hydroxyethyl)-2-methylbenzimidazol-5-yl)-2,4- pyrimidinediamine 904N4- (3,4-Dichlorophenyl)-N2- (2,3-dihydro-1-methyl-2-oxo- LCMS: ret.time: 10.32 min.; purity: 100%; MS (m/e): 420 (MH⁺). − −benzimidazol-5-yl)-5-fluoro-2,4-pyrimidinediamine 905 N4-(3-Chloro-4-methoxyphenyl)-N2- (2,3-dihydro-1-methyl-2- LCMS: ret. time:8.24 min.; purity: 96%; MS (m/e): 415 (MH⁺). + +oxo-benzimidazol-5-yl)-5-fluoro-2,4-pyrimidinediamine 906 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2- (2,3- LCMS: ret. time:7.53 min.; purity: 97%; MS (m/e): 450 (MH⁺). + +dihydro-1-methyl-2-oxo-benzimidazol-5-yl)-5-fluoro-2,4-pyrimidinediamine 907 (S)-N2-(2,3-Dihydro-1-methyl-2-oxo-benzimidazol-5-yl)-5- LCMS: ret. time: 7.00min.; purity: 98%; MS (m/e): 436 (MH⁺). + + fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- pyrimidinediamine 908N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2- (2,3- LCMS: ret.time: 8.19 min.; purity: 94%; MS (m/e): 451 (MH⁺). + +dihydro-1-methyl-2-oxo-benzimidazol-5-yl)-5-fluoro-2,4-pyrimidinediamine 909 5-Fluoro-N2- (2-methyl-3H-benzimidazol-5-yl)-N4-(2-methyl- LCMS: ret. time: 7.11 min.; purity: 94%; MS (m/e): 468(MH⁺). + + 1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 910 5-Fluoro-N4-(2-methyl-1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6- LCMS: ret. time: 10.29min.; purity: 98%; MS (m/e): 521 (MH⁺). + + yl)-N2-(2-trifluoromethyl-1H-benzimidazol-5-yl)-2,4- pyrimidinediamine 911 N4-(3,4-Dichlorophenyl)-5-fluoro-N2- (1-methyl-2- LCMS: ret. time: 14.28min.; purity: 97%; MS (m/e): 472 (MH⁺). +trifluoromethylbenzimidazol-5-yl)-2,4-pyrimidinediamine 912 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2- (1-methyl-2- LCMS: ret. time:11.38 min.; purity: 91%; MS (m/e): 467 (MH⁺). +trifluoromethylbenzimidazol-5-yl)-2,4-pyrimidinediamine 913 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2- (1- LCMS: ret. time:10.21 min.; purity: 94%; MS (m/e): 502 (MH⁺). +methyl-2-trifluoromethylbenzimidazol-5-yl)-2,4- pyrimidinediamine 914(S)-5-Fluoro-N4- (2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)- LCMS: ret.time: 9.66 min.; purity: 93%; MS (m/e): 488 (MH⁺). + N2-(1-methyl-2-trifluoromethylbenzimidazol-5-yl)-2,4- pyrimidinediamine 915N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2- (1- LCMS: ret.time: 11.48 min.; purity: 91%; MS (m/e): 503 (MH⁺). +methyl-2-trifluoromethylbenzimidazol-5-yl)-2,4- pyrimidinediamine 916N4- (3,4-Dichlorophenyl)-5-fluoro-[1- (2-hydroxyethyl)-2- LCMS: ret.time: 12.15 min.; purity: 96%; MS (m/e): 502 (MH⁺). +trifluoromethylbenzimidazol-5-yl]-2,4-pyrimidinediamine 917 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-[1- (2-hydroxyethyl)-2- LCMS: ret.time: 9.90 min.; purity: 94%; MS (m/e): 497 (MH⁺). +trifluoromethylbenzimidazol-5-yl]-2,4-pyrimidinediamine 918 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-[1- LCMS: ret.time: 9.08 min.; purity: 96%; MS (m/e): 532 (MH⁺). + +(2-hydroxyethyl)-2-trifluoromethylbenzimidazol-5-yl]-2,4-pyrimidinediamine 919 (S)-5-Fluoro-[1-(2-hydroxyethyl)-2-trifluoromethylbenzimidazol- LCMS: ret. time: 8.67min.; purity: 92%; MS (m/e): 518 (MH⁺). + + 5-yl]-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- pyrimidinediamine 920N4- (3,4-Dichlorophenyl)-5-fluoro-[1- (2-hydroxymethyl)-2- LCMS: ret.time: 14.96 min.; purity: 97%; MS (m/e): 486 (MH⁺). + +trifluoromethylbenzimidazol-5-yl]-2,4-pyrimidinediamine 921 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-[1- (2-hydroxymethyl)- LCMS: ret.time: 12.21 min.; purity: 98%; MS (m/e): 481 (MH⁺). + +2-trifluoromethylbenzimidazol-5-yl]-2,4-pyrimidinediamine 922 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-[1- LCMS: ret.time: 10.93 min.; purity: 96%; MS (m/e): 516 (MH⁺). +(2-hydroxymethyl)-2-trifluoromethylbenzimidazol-5-yl]-2,4-pyrimidinediamine 923 (S)-5-Fluoro-[1- (2-hydroxymethyl)-2- LCMS: ret.time: 10.43 min.; purity: 92%; MS (m/e): 502 (MH⁺). +trifluoromethylbenzimidazol-5-yl]-N4- (2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 924 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-[1- LCMS: ret.time: 12.25 min.; purity: 98%; MS (m/e): 517 (MH⁺). +(2-hydroxymethyl)-2-trifluoromethylbenzimidazol-5-yl]-2,4-pyrimidinediamine 925 N2- (1,2-Benzisoxazol-5-yl)-N4-(3-chloro-4-methoxyphenyl)-5- LCMS: ret. time: 9.63 min.; purity: 100%;MS (m/e): 386 (MH⁺). + fluoro-2,4-pyrimidinediamine 926 N2-(1,2-Benzisoxazol-5-yl)-N4- (2,2-dimethyl-3-oxo-4H- LCMS: ret. time:8.48 min.; purity: 100%; MS (m/e): 421 (MH⁺). +benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 927 (S)-N2-(1,2-Benzisoxazol-5-yl)-5-fluoro-N4- (2-methyl-3-oxo- LCMS: ret. time:8.11 min.; purity: 100%; MS (m/e): 407 (MH⁺). +2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 928 N2-(1,2-Benzisoxazol-5-yl)-N4- (2,2-dimethyl-3-oxo-4H-5- LCMS: ret. time:9.57 min.; purity: 100%; MS (m/e): 422 (MH⁺). +pyrido[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 929 racemic-N2-(1,2-Benzisoxazol-5-yl)-5-fluoro- (2-methyl-1,1,3- LCMS: ret. time: 9.69min.; purity: 95%; MS (m/e): 455 (MH⁺). +trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 930 N2-(1,2-Benzisoxazol-5-yl)-N4- (2,2-dimethyl-1,1,3-trioxo-4H- LCMS: ret.time: 10.13 min.; purity: 97%; MS (m/e): 470 (MH⁺). +benzo[1,4]thiazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 931 racemic-N2-(1,2-Benzisoxazol-5-yl)-5-fluoro-N4- (2-methyl-3- LCMS: ret. time: 9.21min.; purity: 96%; MS (m/e): 423 (MH⁺). + oxo-2H,4H-benz[1,4]thiazin-6-yl)-2,4-pyrimidinediamine 932 N4-(3,4-Dichlorophenyl)-N2- (1-ethyl-2-methylbenzimidazol-5- LCMS: ret.time: 10.09 min.; purity: 99%; MS (m/e): 432 (MH⁺). −yl)-5-fluoro-2,4-pyrimidinediamine 933 N4-(3-Chloro-4-methoxyphenyl)-N2- (1-ethyl-2- LCMS: ret. time: 8.64 min.;purity: 92%; MS (m/e): 427 (MH⁺). +methylbenzimidazol-5-yl)-5-fluoro-2,4-pyrimidinediamine 934 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-N2- (1-ethyl- LCMS: ret.time: 7.91 min.; purity: 99%; MS (m/e): 462 (MH⁺). +2-methylbenzimidazol-5-yl)-5-fluoro-2,4-pyrimidinediamine 935 (S)-N2-(1-Ethyl-2-methylbenzimidazol-5-yl)-5-fluoro-N4- (2- LCMS: ret. time:7.72 min.; purity: 95%; MS (m/e): 448 (MH⁺). + +methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- pyrimidinediamine 936 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-N2- (1- LCMS: ret.time: 8.48 min.; purity: 96%; MS (m/e): 463 (MH⁺). +ethyl-2-methylbenzimidazol-5-yl)-5-fluoro-2,4- pyrimidinediamine 937 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1- (3-hydroxypropyl)-2- LCMS: ret.time: 12.33 min.; purity: 97%; MS (m/e): 516 (MH⁺). + +trifluoromethylbenzimidazol-5-yl]-2,4-pyrimidinediamine 938 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1- (3- LCMS: ret. time: 9.85min.; purity: 94%; MS (m/e): 511 (MH⁺). +hydroxypropyl)-2-trifluoromethylbenzimidazol-5-yl]-2,4-pyrimidinediamine 939 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- LCMS: ret.time: 9.04 min.; purity: 96%; MS (m/e): 546 (MH⁺). + + [1-(3-hydroxypropyl)-2-trifluoromethylbenzimidazol-5-yl]-2,4-pyrimidinediamine 940 (S)-5-Fluoro-N2-[1- (3-hydroxypropyl)-2- LCMS:ret. time: 8.49 min.; purity: 95%; MS (m/e): 532 (MH⁺). + +trifluoromethylbenzimidazol-5-yl]-N4- (2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)- -2,4-pyrimidinediamine 941 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro- LCMS: ret.time: 9.85 min.; purity: 93%; MS (m/e): 547 (MH⁺). + + N2-[1-(3-hydroxypropyl)-2-trifluoromethylbenzimidazol-5-yl]-2,4-pyrimidinediamine 942 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-methyl-2- (4- LCMS: ret. time: 9.49min.; purity: 97%; MS (m/e): 489 (MH⁺). + + +morpholino)benzimidazol-5-yl]-2,4-pyrimidinediamine 943 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-methyl-2- (4- LCMS: ret. time:7.79 min.; purity: 93%; MS (m/e): 484 (MH⁺). + +morpholino)benzimidazol-5-yl]-2,4-pyrimidinediamine 944 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- LCMS: ret.time: 7.20 min.; purity: 99%; MS (m/e): 519 (MH⁺). + + + [1-methyl-2-(4-morpholino)benzimidazol-5-yl]-2,4- pyrimidinediamine 945(S)-5-Fluoro-N2-[1-methyl-2- (4-morpholino)benzimidazol-5- LCMS: ret.time: 6.78 min.; purity: 90%; MS (m/e): 505 (MH⁺). + + yl]-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- pyrimidinediamine 946N4- (2,2-Dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro- LCMS:ret. time: 7.86 min.; purity: 96%; MS (m/e): 520 (MH⁺). + +N2-[1-methyl-2- (4-morpholino)benzimidazol-5-yl]-2,4- pyrimidinediamine947 N4- (3,4-Dichlorophenyl)-5-fluoro-N2-[1- (3-hydroxypropyl)-2- LCMS:ret. time: 9.65 min.; purity: 95%; MS (m/e): 462 (MH⁺). +methylbenzimidazol-5-yl]-2,4-pyrimidinediamine 948 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1- (3- LCMS: ret. time: 8.28min.; purity: 90%; MS (m/e): 457 (MH⁺). +hydroxypropyl)-2-methylbenzimidazol-5-yl]-2,4- pyrimidinediamine 949 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- LCMS: ret.time: 7.70 min.; purity: 96%; MS (m/e): 492 (MH⁺). + [1-(3-hydroxypropyl)-2-methylbenzimidazol-5-yl]-2,4- pyrimidinediamine 950(S)-5-Fluoro-N2-[1- (3-hydroxypropyl)-2-methylbenzimidazol-5- LCMS: ret.time: 7.22 min.; purity: 90%; MS (m/e): 478 (MH⁺). + yl]-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- pyrimidinediamine 951N4- (2,2-Dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro- LCMS:ret. time: 7.97 min.; purity: 94%; MS (m/e): 493 (MH⁺). + + N2-[1-(3-hydroxypropyl)-2-methylbenzimidazol-5-yl]-2,4- pyrimidinediamine 952N2-[1-[3- (N-Acetylamino)propyl]-2-methylbenzimidazol-5-yl]- LCMS: ret.time: 7.89 min.; purity: 97%; MS (m/e): 533 (MH⁺). + + N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 953 N2-[1-[3-(N-Acetylamino)propyl]-2-methylbenzimidazol-5-yl]- LCMS: ret. time: 8.09min.; purity: 97%; MS (m/e): 534 (MH⁺). + + N4-(2,2-Dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 954 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-methyl-2- (4- LCMS: ret. time: 10.04min.; purity: 96%; MS (m/e): 503 (MH⁺). + +morpholinomethyl)benzimidazol-5-yl]-2,4-pyrimidinediamine 955 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-methyl-2- (4- LCMS: ret. time:9.29 min.; purity: 93%; MS (m/e): 498 (MH⁺). +morpholinomethyl)benzimidazol-5-yl]-2,4-pyrimidinediamine 956 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- LCMS: ret.time: 8.09 min.; purity: 94%; MS (m/e): 533 (MH⁺). + [1-methyl-2-(4-morpholinomethyl)benzimidazol-5-yl]-2,4- pyrimidinediamine 957(S)-5-Fluoro-N2-[1-methyl-2- (4- LCMS: ret. time: 7.55 min.; purity:98%; MS (m/e): 519 (MH⁺). + + morpholinomethyl)benzimidazol-5-yl]-N4-(2-methyl-3-oxo- 2H,4H-benz[1,4]oxazin-6-yl)- -2,4-pyrimidinediamine 958N4- (2,2-Dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro- LCMS:ret. time: 8.34 min.; purity: 98%; MS (m/e): 534 (MH⁺). +N2-[1-methyl-2- (4-morpholinomethyl)benzimidazol-5-yl]-2,4-pyrimidinediamine 959 N4- (3,4-Dichlorophenyl)-5-fluoro-N2-[2-(4-morpholinomethyl)- LCMS: ret. time: 9.12 min.; purity: 95%; MS (m/e):489 (MH⁺). + 1H-benzimidazol-5-yl]-2,4-pyrimidinediamine 960 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[2- (4- LCMS: ret. time: 8.10min.; purity: 97%; MS (m/e): 484 (MH⁺). +morpholinomethyl)-1H-benzimidazol-5-yl]-2,4- pyrimidinediamine 961 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- LCMS: ret.time: 7.70 min.; purity: 93%; MS (m/e): 519 (MH⁺). + + [2-(4-morpholinomethyl)-1H-benzimidazol-5-yl]-2,4- pyrimidinediamine 962N4- (2,2-Dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro- LCMS:ret. time: 7.93 min.; purity: 95%; MS (m/e): 520 (MH⁺). + + N2-[2-(4-morpholinomethyl)-1H-benzimidazol-5-yl]-2,4- pyrimidinediamine 963N4- (2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- LCMS: ret.time: 8.01 min.; purity: 95%; MS (m/e): 569 (MH⁺). + [2-methyl-1-[3-(N-methylsulfonylamino)propyl]benzimidazol-5- yl]-2,4-pyrimidinediamine964 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro- LCMS:ret. time: 8.36 min.; purity: 95%; MS (m/e): 570 (MH⁺). + +N2-[2-methyl-1-[3- (N-methylsulfonylamino)propyl]benzimidazol-5-yl]-2,4- pyrimidinediamine 965N4- (3,4-Dichlorophenyl)-5-fluoro-N2-{1-methyl-2- LCMS: ret. time: 10.63min.; purity: 94%; MS (m/e): 496 (MH⁺). + [(methylsulfonyl)methyl]benzimidazol-5-yl}-2,4- pyrimidinediamine 966 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-{1-methyl-2- LCMS: ret. time:9.10 min.; purity: 95%; MS (m/e): 491 (MH⁺). + [(methylsulfonyl)methyl]benzimidazol-5-yl}-2,4- pyrimidinediamine 967 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- LCMS: ret.time: 9.22 min.; purity: 91%; MS (m/e): 525 (MH⁺). + + {1-methyl-2-[(methylsulfonyl)methyl]benzimidazol-5-yl}-2,4- pyrimidinediamine 968(S)-5-Fluoro-N2-{1-methyl-2- LCMS: ret. time: 8.62 min.; purity: 91%; MS(m/e): 512 (MH⁺). + + [ (methylsulfonyl)methyl]benzimidazol-5-yl}-N4-(2-methyl-3- oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 969N4- (2,2-Dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro- LCMS:ret. time: 9.14 min.; purity: 94%; MS (m/e): 527 (MH⁺). + +N2-{1-methyl-2-[ (methylsulfonyl)methyl]benzimidazol-5-yl}-2,4-pyrimidinediamine 970 N4- (3,4-Dichlorophenyl)-N2-[2-(N,N-diethylaminomethyl)-1- LCMS: ret. time: 9.42 min.; purity: 91%; MS(m/e): 489 (MH⁺). +methylbenzimidazol-5-yl]-5-fluoro-2,4-pyrimidinediamine 971 N4-(3-Chloro-4-methoxyphenyl)-N2-[2- (N,N- LCMS: ret. time: 7.76 min.;purity: 94%; MS (m/e): 485 (MH⁺). +diethylaminomethyl)-1-methylbenzimidazol-5-yl]-5-fluoro-2,4-pyrimidinediamine 972 N2-[2-(N,N-Diethylaminomethyl)-1-methylbenzimidazol-5-yl]- LCMS: ret. time:7.56 min.; purity: 94%; MS (m/e): 519 (MH⁺). + + N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 973 (S)-N2-[2-(N,N-Diethylaminomethyl)-1-methylbenzimidazol-5- LCMS: ret. time: 7.21min.; purity: 97%; MS (m/e): 505 (MH⁺). + + yl]-5-fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)- 2,4-pyrimidinediamine 974N2-[2- (N,N-Diethylaminomethyl)-1-methylbenzimidazol-5-yl]- LCMS: ret.time: 7.51 min.; purity: 97%; MS (m/e): 520 (MH⁺). + + N4-(2,2-dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 975 N4- (3,4-Dichlorophenyl)-5-fluoro-N2-[2-(4-morpholino)-1H- LCMS: ret. time: 8.89 min.; purity: 90%; MS (m/e):475 (MH⁺). + + benzimidazol-5-yl]-2,4-pyrimidinediamine 976 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- LCMS: ret.time: 7.76 min.; purity: 96%; MS (m/e): 505 (MH⁺). + + [2-(4-morpholino)-1H-benzimidazol-5-yl]-2,4-pyrimidinediamine 977 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro- LCMS: ret.time: 8.05 min.; purity: 926%; MS (m/e): 506 (MH⁺). + + N2-[2-(4-morpholino)-1H-benzimidazol-5-yl]-2,4- pyrimidinediamine 978 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[2- (4-morpholino)- LCMS: ret.time: 8.03 min.; purity: 92%; MS (m/e): 470 (MH⁺). +1H-benzimidazol-5-yl]-2,4-pyrimidinediamine 979 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[1-methyl-2- (4-methyl-1- LCMS: ret.time: 8.12 min.; purity: 98%; MS (m/e): 502 (MH⁺). piperazino)-1H-benzimidazol-5-yl]-2,4-pyrimidinediamine 980 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[1-methyl-2- (4- LCMS: ret. time:7.34 min.; purity: 96%; MS (m/e): 497 (MH⁺).methyl-1-piperazino)-1H-benzimidazol-5-yl]-2,4- pyrimidinediamine 981N4- (2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- LCMS: ret.time: 6.99 min.; purity: 97%; MS (m/e): 532 (MH⁺). [1-methyl-2-(4-methyl-1-piperazino)-1H-benzimidazol-5-yl]-2,4- pyrimidinediamine 982(S)-5-Fluoro-N2-[1-methyl-2- (4-methyl-1-piperazino)-1H- LCMS: ret.time: 6.62 min.; purity: 97%; MS (m/e): 518 (MH⁺).benzimidazol-5-yl]-N4- (2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 983 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrido[1,4]oxazin-6-yl)-5-fluoro- LCMS: ret.time: 7.05 min.; purity: 96%; MS (m/e): 533 (MH⁺). N2-[1-methyl-2-(4-methyl-1-piperazino)-1H-benzimidazol-5-yl]- 2,4-pyrimidinediamine 984N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- ¹H NMR(DMSO-d6): d 11.22 (1H, s), 9.79 (1H, s), 9.62 (1H, s), 8.27 + + +N2-[3- (N-methylamino)carbonylmethyleneoxyphenyl]-2,4- (1H, d, J = 3.9Hz), 8.08 (1H, d, J = 4.5 Hz), 7.68-7.64 (3H, m), 7.47 pyrimidinediamineBenzensulfonic Acid Salt (1H, d, J = 8.7 Hz), 7.42-7.31 (5H, m), 7.22(1H, t, J = 8.1 Hz), 6.63 (1H, dd, J = 8.1 Hz, J = 2.4 Hz), 4.47 (2H,985 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- ¹H NMR(DMSO-d6): d 11.23 (1H, s), 9.91 (1H, s), 9.70 (1H, s), 8.29 + + +N2-[3- (N-methylamino)carbonylmethyleneoxyphenyl]-2,4- (1H, d, J = 3.9Hz), 8.06 (1H, m), 7.65-7.61 (1H, m), 7.55 (1H, d, J = pyrimidinediaminep-Toluenesulfonic Acid Salt 8.1 Hz), 7.48 (1H, d, J = 8.1 Hz), 7.33-7.18(5H, m), 6.66 (1H, d, J = 7.5 Hz), 4.48 (2H, s), 2.75 (3H, d, J = 3.6986 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- ¹H NMR(DMSO-d6): d 11.18 (1H, s), 9.54 (2H, broad s), 8.26 (1H, + + N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- s), 8.05 (1H, broad s),7.70-7.66 (1H, m), 7.47 (1H, d, J = 8.4 Hz), 7.40 pyrimidinediamineHydrogen Chloride Salt (1H, s), 7.34 (1H, d, J = 9 Hz), 7.20 (1H, t, J =7.9 Hz), 6.61 (1H, d, J = 7.5 Hz), 4.47 (2H, s), 2.75 (3H, d, J 987 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- ¹H NMR(DMSO-d6): d 11.18 (1H, s), 9.50 (2H, broad s), 8.25 (1H, + + N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- d, J = 3.3 Hz), 8.06(1H, m), 7.74-7.67 (1H, m), 7.47 (1H, d, J = 8.4 pyrimidinediamineBis-Hydrogen Chloride Salt Hz), 7.41 (1H, s), 7.37 (1H, d, J = 8.1 Hz),7.20 (1H, t, J = 7.9 Hz), 6.59 (1H, d, J = 8.1 Hz), 4.47 (2H, s), 2.74 (988 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- ¹H NMR(DMSO-d6): d 11.19 (1H, s), 9.58 (1H, broad s), 9.52 (1H, + + N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- s), 8.25 (1H, d, J = 3.6Hz), 8.06 (1H, m), 7.70-7.66 (1H, m), 7.47 (1H, pyrimidinediamine NitricAcid Salt d, J = 8.7 Hz), 7.40 (1H, s), 7.34 (1H, d, J = 8.1 Hz), 7.21(1H, t, J = 8.1 Hz), 6.61 (1H, d, J = 7.5 Hz), 4.47 ( 989 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- ¹H NMR(DMSO-d6): d 11.21 (1H, s), 9.64 (1H, broad s), 9.54 (1H, s), + + N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- 8.26 (1H, d, J = 3.6Hz), 8.07 (1H, m), 7.67 (1H, d, J = 8.4 Hz), 7.47 pyrimidinediamineBis-Nitric Acid Salt (1H, d, J = 8.7 Hz), 7.39 (1H, s), 7.34 (1H, d, J =7.8 Hz), 7.21 (1H, t, J = 8.2 Hz), 6.62 (1H, d, J = 8.4 Hz), 4 990 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- ¹H NMR(DMSO-d6): d 11.24 (1H, s), 9.79 (1H, broad s), 9.63 (1H, + + N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- s), 8.27 (1H, d, J = 3.9Hz), 8.07 (1H, m), 7.64 (1H, d, J = 8.4 Hz), 7.48 pyrimidinediamineMethanesulfonic Acid Salt (1H, d, J = 8.4 Hz), 7.36 (1H, s), 7.32 (1H,d, J = 7.5 Hz), 7.22 (1H, t, J = 7.9 Hz), 6.64 (1H, d, J = 8.7 Hz), 991N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- ¹H NMR(DMSO-d6): d 11.25 (1H, s), 9.72 (1H, brad s), 9.59 (1H, s), + + N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- 8.27 (1H, d, J = 3.6Hz), 8.07 (1H, m), 7.65 (1H, d, J = 8.4 Hz), 7.47 pyrimidinediamine(1S)- (+)-Camphorsulfonic Acid Salt (1H, d, J = 8.7 Hz), 7.37 (1H, s),7.33 (1H, d, J = 8.7 Hz), 7.21 (1H, t, J = 8.1 Hz), 6.62 (1H, dd, J =8.1 Hz, J 992 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- ¹H NMR(DMSO-d6): d 11.21 (1H, s), 9.63 (1H, brad s), 9.54 (1H, s), + + −N2-[3- (N-methylamino)carbonylmethyleneoxyphenyl]-2,4- 8.26 (1H, d, J =3.6 Hz), 8.07 (1H, m), 7.67 (1H, d, J = 8.4 Hz), 7.47 pyrimidinediamine(+)-Camphorsulfonic Acid Salt (1H, d, J = 8.7 Hz), 7.39 (1H, s), 7.34(1H, d, J = 8.1 Hz), 7.21 (1H, t, J = 8.1 Hz), 6.61 (1H, dd, J = 8.1 Hz,J 993 N4- (2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- ¹HNMR (DMSO-d6): d 10.78 (1H, s), 10.11 (1H, broad s), 9.89 (1H, + + +(1-methylindazol-6-yl)-2,4-pyrimidinediamine p- broad s), 8.29 (1H, d, J= 4.8 Hz), 8.01 (1H, s), 7.95 (1H, s), 7.70 (1H, Toluenesulfonic AcidSalt d, J = 8.7 Hz), 7.55 (2H, d, J = 8.1 Hz), 7.40 (1H, d, J = 8.4 Hz),7.29- 7.18 (4H, m), 6.95 (1H, d, J = 8.7 Hz), 994 N2-(3-Chloro-4-methoxy-5-methylphenyl)-N4- (2,2-dimethyl-3- ¹H NMR(DMSO-d6): d 10.73 (1H, s), 9.65 (1H, s), 9.41 (1H, s), 8.20 + + + +oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine (1H, d, J =4.2 Hz), 7.71 (1H, s), 7.54 (2H, d, J = 8.1 Hz), 7.43 (1H, s),p-Toluenesulfonic Acid Salt 7.35 (1H, dd, J = 8.4 Hz, J = 2.4 Hz),7.23-7.17 (3H, m), 7.00 (1H, d, J = 8.4 Hz), 3.76 (3H, s), 2.38 (3H, s)995 N2- (3-Chloro-4-hydroxy-5-methylphenyl)-N4- (3,4- ¹H NMR (DMSO-d6):d9.19 (1H, d, J = 1.5 Hz), 9.05 (1H, s), 8.64 (1H, + + +ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine s), 8.10 (1H, d, J =3.9 Hz), 7.62 (1H, d, J = 2.7 Hz), 7.36 (1H, d, J = 1.8 Hz), 7.31 (1H,m), 7.27 (1H, d, J = 2.7 Hz), 6.87 (1H, d, J = 8.4 Hz), 4.31 (4H, s),2.22 (3H, s); LCMS: purity: 996 N2-(3-Chloro-4-hydroxy-5-methylphenyl)-N4- (2,2-dimethyl-3- ¹H NMR(DMSO-d6): d 11.16 (1H, s), 9.27 (1H, s), 9.15 (1H, s), 8.67 + + −oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine (1H, s),8.19 (1H, d, J = 3.6 Hz), 7.64 (2H, m), 7.42 (1H, d, J = 8.4 Hz), 7.29(1H, d, J = 2.7 Hz), 2.22 (3H, s), 1.53 (6H, s); LCMS: purity: 97.69%;MS (m/e): 444 (M+). 997 N2- (3,5-Dimethyl-4-methoxyphenyl)-N4-(2,2-dimethyl-3-oxo- ¹H NMR (DMSO-d6): d 11.16 (1H, s), 9.23 (1H, s),9.11 (1H, s), 8.19 + + − +4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine (1H, d, J =3.6 Hz), 7.69 (1H, d, J = 8.1 Hz), 7.44 (1H, d, J = 8.4 Hz), 7.33 (2H,s), 3.68 (3H, s), 2.23 (6H, s), 1.53 (6H, s); LCMS: purity: 99%; MS(m/e): 439 (MH+). 998 N2- (3,5-Dimethyl-4-methoxyphenyl)-N4- (3,4- ¹HNMR (DMSO-d6): d 10.06 (1H, s), 9.85 (1H, s), 8.25 (1H, d, J = 4.8 + + −ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine Hz), 7.33 (1H, d, J= 2.4 Hz), 7.24 (2H, s), 7.20 (1H, d, J = 2.7 Hz), 6.91 (1H, d, J = 8.4Hz), 4.32 (4H, s), 3.71 (3H, s), 2.25 (6H, s); LCMS: purity: 96.69%; MS(m/e): 397 (MH+). 999 N2- (3-Chloro-4-methoxy-5-methylphenyl)-N4- (3,4-¹H NMR (DMSO-d6): d 9.88 (2H, broad s), 8.26 (1H, d, J = 4.2 Hz), + + +ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.64 (1H, s), 7.41(1H, s), 7.30-7.28 (1H, m), 7.25-7.20 (1H, m), 6.92 (1H, d, J = 10.2Hz), 4.32 (4H, s), 3.79 (3H, s), 2.29 (3H, s); LCMS: purity: 94.81%; MS(m/e): 417 (MH+). 1000 N4-(3,4-Dihydro-2,2-dimethyl-4H-benz[1,4]oxazin-6-yl)-5- ¹H NMR (DMSO-d6):d 9.15 (1H, s), 9.08 (1H, s), 8.09 (1H, d, J = 3.6 + fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]- Hz), 8.04 (1H, d, J = 4.5Hz), 7.45-7.42 (2H, m), 7.17 (1H, t, J = 8.4 2,4-pyrimidinediamine Hz),7.01 (1H, d, J = 2.4 Hz), 6.95 (1H, d, J = 8.4 Hz), 6.65 (1H, d, J = 8.7Hz), 6.53 (1H, d, J = 9.3 Hz), 5.88 1001 N2-(3-Chloro-4-methoxy-5-methylphenyl)-N4- (3,4-dihydro-2,2- ¹H NMR(DMSO-d6): d 9.59 (1H, broad s), 8.17 (1H, d, J = 4.2 Hz), +dimethyl-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4- 7.65 (1H, s), 7.46 (1H,s), 6.94-6.86 (2H, m), 6.68 (1H, d, J = 8.7 Hz), pyrimidinediamine 3.77(3H, s), 3.08 (2H, s), 2.27 (3H, s), 1.34 (6H, s); purity: 94.5%; MS(m/e): 444 (M). 1002 N4-(3,4-Dihydro-2,2-dimethyl-4H-benz[1,4]oxazin-6-yl)-N2- ¹H NMR (DMSO-d6):d 9.06 (2H, s), 8.09 (1H, d, J = 3.6 Hz), 7.03 +(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (1H, dd, J = 6.9Hz, J = 1.8 Hz), 6.95 (1H, dd, J = 8.1 Hz, J = 2.7 Hz), 6.63 (1H, d, J =8.7 Hz), 6.11 (1H, s), 5.82 (1H, s), 3.71 (6H, s), 3.07 (2H, s), 1.34(6H, s); purity 95.9%; MS ( 1003 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- ¹H NMR(DMSO-d6): d 11.17 (1H, s), 9.27 (1H, s), 9.24 (1H, s), 8.21 + + N2-(3-isopropylphenyl)-2,4-pyrimidinediamine (1H, d, J = 3.6 Hz), 7.67 (1H,m), 7.61 (1H, d, J = 9 Hz), 7.52 (1H, s), 7.44 (1H, d, J = 8.7 Hz), 7.19(1H, t, J = 7.65 Hz), 6.85 (1H, d, J = 7.8 Hz), 2.82 (1H, m), 1.53 (6H,s), 1.25 1004 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- ¹H NMR(DMSO-d6): d 11.23 (1H, s), 10.12 (1H, s), 9.39 (1H, s), + − N2-(2-methylphenyl)-2,4-pyrimidinediamine 8.27 (1H, d, J = 4.8 Hz), 7.52(1H, d, J = 6.9 Hz), 7.43 (1H, d, J = 8.7 Hz), 7.34-7.16 (4H, m), 2.30(3H, s), 1.50 (6H, s); purity 97.9%; MS (m/e): 395 (MH+). 10052-Chloro-5-fluoro-N4-methyl-N4- (3-oxo-2,2,4-trimethyl-5- 1H NMR(DMSO-d6): d 8.43 (1H, d, J = 5.1 Hz), 7.57 (1H, d, J = 8.4 + −pyrid[1,4]oxazin-6-yl)-4-pyrimidineamine Hz), 7.15 (1H, dd, J = 8.1 Hz,J = 0.9 Hz), 3.59 (3H, s), 3.30 (3H, s), 1.55 (6H, s); purity 97.2%; MS(m/e): 352 (MH+). 1006 2-Chloro-5-fluoro-N4-(3-oxo-2,2,4-trimethyl-5-pyrid[1,4]oxazin- 1H NMR (DMSO-d6): d 10.35(1H, s), 8.47 (1H, d, J = 3.3 Hz), 7.62 − − 6-yl)-4-pyrimidineamine (1H,d, J = 8.7 Hz), 7.58 (1H, d, J = 8.4 Hz), 3.45 (3H, s), 1.55 (6H, s);purity 96%; MS (m/e): 338 (MH+). 1007 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 11.14 (1H, s), 9.24 (1H, s), 9.19 (1H, s), 8.21 + + − + N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine (1H, d, J = 3.3 Hz), 7.76(1H, d, J = 8.7 Hz), 7.41 (1H, d, J = 8.7 Hz), 7.12 (2H, s), 3.75 (6H,s), 3.69 (3H, s), 1.52 (6H, s); purity 96%; MS (m/e): 471 (MH+) 1008 N2-(3-Chloro-4-ethoxy-5-methylphenyl)-N4- (2,2-dimethyl-3- ¹H NMR(DMSO-d6): d 10.67 (1H, s), 9.40 (1H, s), 9.20 (1H, s), 8.16 + + + +oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine (1H, d, J =3.9 Hz), 7.74 (1H, d, J = 3 Hz), 7.45 (1H, d, J = 2.7 Hz), 7.36 (1H, dd,J = 8.7 Hz, J = 2.4 Hz), 7.25 (1H, d, J = 2.4 Hz), 6.98 (1H, d, J = 8.7Hz), 3.94 (2H, q, J = 7.2 Hz 1009 N2-(3-Chloro-4-methoxy-5-methylphenyl)-5-fluoro-N4- (3-oxo- 1H NMR(DMSO-d6): d 9.62 (1H, s), 9.41 (1H, s), 8.27 (1H, s), 7.80 + + −2,2,4-trimethyl-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine (1H, s),7.73 (1H, d, J = 8.7 Hz), 7.48 (1H, d, J = 8.7 Hz), 7.43 (1H, s), 3.78(3H, d, J = 2.4 Hz), 2.92 (3H, s), 1.55 (6H, d, J = 2.4 Hz); purity 97%;MS (m/e): 473 (MH+). 1010 N2- (3-Chloro-4-ethoxy-5-methylphenyl)-N4-(2,2-dimethyl-3- 1H NMR (DMSO-d6): d 11.18 (1H, s), 9.41 (1H, s), 9.38(1H, s), 8.23 + −oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine (1H, d, J= 3.6 Hz), 7.74 (1H, d, J = 2.7 Hz), 7.61 (1H, d, J = 8.4 Hz), 7.46 (1H,d, J = 8.1 Hz), 7.41 (1H, d, J = 2.1 Hz), 3.95 (2H, q, J = 7.2 Hz), 2.27(3H, s), 1.53 (6H, s), 1.42 ( 1011 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 10.74 (1H, s), 9.56 (1H, s), 9.49 (1H, s), + + − + [4-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 8.21-8.19 (2H, m), 7.89 (2H,d, J = 9 Hz), 7.84 (2H, d, J = 9 Hz), 7.37 (1H, d, J = 0.6 Hz), 7.33(1H, dd, J = 8.1 Hz, J = 2.4 Hz), 7.26 (1H, d, J = 2.7 Hz), 7.02 (1H, d,J = 8.7 Hz), 1.53 ( 1012 5-Fluoro-N2-[3-(oxazol-2-yl)phenyl]-N4-[3-oxo-2,2,4-trimethyl- 1H NMR (DMSO-d6): d 9.76(1H, s), 9.74 (1H, s), 8.41 (1H, s), 8.32 + + −5-pyrid[1,4]oxazin-6-yl]-2,4-pyrimidinediamine (1H, d, J = 3.6 Hz), 8.25(1H, s), 7.89-7.83 (2H, m), 7.64 (1H, d, J = 7.8 Hz), 7.48 (1H, d, J =7.8 Hz), 7.44 (1H, s), 7.36 (1H, d, J = 7.2 Hz), 3.42 (3H, s), 1.54 (6H,s); purity 96%. 1013 5-Fluoro-N2-[4-(oxazol-2-yl)phenyl]-N4-[3-oxo-2,2,4-trimethyl- 1H NMR (DMSO-d6): d 9.76(1H, s), 9.73 (1H, s), 8.31 (1H, d, J = 3.6 + −5-pyrid[1,4]oxazin-6-yl]-2,4-pyrimidinediamine Hz), 8.21 (1H, d, J = 0.9Hz), 7.92 (2H, d, J = 9.3 Hz), 7.88 (2H, d, J = 9.6 Hz), 7.76 (1H, d, J= 8.4 Hz), 7.54 (1H, d, J = 8.4 Hz), 7.38 (1H, d, J = 0.9 Hz), 3.44 (3H,s), 1.57 (6H, 1014N2-[3-Chloro-4-ethoxycarbonylmethyleneoxy-5-methylphenyl]- 1H NMR(DMSO-d6): d 10.69 (1H, s), 9.43 (1H, s), 9.27 (1H, s), 8.17 + + + N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4- (1H, d, J =3.6 Hz), 7.76 (1H, d, J = 2.7 Hz), 7.46 (1H, d, J = 2.4 Hz),pyrimidinediamine 7.36 (1H, dd, J = 9 Hz, J = 2.7 Hz), 7.24 (1H, d, J =2.4 Hz), 6.99 (1H, d, J = 8.4 Hz), 4.58 (2H, s), 4.28 (2H, 10155-Fluoro-N2-[3- (N-methylamino)carbonylmethyleneoxyphenyl]- 1H NMR(DMSO-d6): d 9.58 (1H, s), 9.42 (1H, s), 8.25 (1H, d, J = 3.3 + + −N4-[3-oxo-2,2,4-trimethyl-5-pyrid[1,4]oxazin-6-yl]-2,4- Hz), 8.06 (1H,broad s), 7.88 (1H, d, J = 8.4 Hz), 7.49 (2H, m), 7.36 pyrimidinediamine(1H, d, J = 7.5 Hz), 7.20 (1H, t, J = 8.1 Hz), 6.56 (1H, dd, J = 8.4 Hz,J = 2.4 Hz), 4.46 (2H, s), 3.44 (3H, s), 1016 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 10.67 (1H, s), 9.53 (1H, s), 9.38 (1H, s), 8.47 + + − + [3-(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine (1H, s), 8.20 (1H, d, J = 3.6Hz), 8.04 (1H, s), 7.78 (1H, m), 7.58 (1H, s), 7.41 (1H, dd, J = 8.7 Hz,J = 2.4 Hz), 7.35 (2H, d, J = 4.8 Hz), 7.29 (1H, d, J = 2.4 Hz), 6.89(1H, d, J= 1017 5-Fluoro-N2-[3-(oxazol-5-yl)phenyl]-N4-[3-oxo-2,2,4-trimethyl- 1H NMR (DMSO-d6): d 9.65(1H, s), 9.57 (1H, s), 8.47 (1H, s), 8.29 + + −5-pyrid[1,4]oxazin-6-yl]-2,4-pyrimidinediamine (1H, d, J = 3.6 Hz), 8.12(1H, s), 8.84 (1H, d, J = 8.1 Hz), 7.74 (1H, m), 7.62 (1H, s), 7.43-7.32(3H, m), 3.42 (3H, s), 1.54 (6H, s); purity 96.4%; MS (m/e): 462 (MH+).1018 N2-[3-Chloro-4-cyclopentyloxy-5-methylphenyl]-N4- (2,2- 1H NMR(DMSO-d6): d 10.68 (1H, s), 9.41 (1H, s), 9.20 (1H, s), 8.16 + + −dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4- (1H, d, J = 3.6Hz), 7.73 (1H, d, J = 2.7 Hz), 7.45 (1H, d, J = 2.4 Hz),pyrimidinediamine 7.36 (1H, dd, J = 9 Hz, J = 2.7 Hz), 7.24 (1H, d, J =2.4 Hz), 6.98 (1H, d, J = 8.7 Hz), 4.65 (1H, m), 2.23 (3H, 1019 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N4- 1H NMR(DMSO-d6): d 10.72 (1H, s), 9.65 (1H, s), 8.71 (1H, s), 8.27 + + −methyl-N2-[3- (oxazol-2-yl)phenyl]-2,4-pyrimidinediamine (1H, t, J = 1.2Hz), 8.09 (1H, dd, J = 5.4 Hz, J = 0.9 Hz), 7.82 (1H, dd, J = 8.1 Hz, J= 0.9 Hz), 7.60 (1H, d, J = 8.4 Hz), 7.48-7.43 (2H, m), 7.05-6.97 (2H,m), 6.87 (1H, d, J = 2.1 H 1020 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 10.75 (1H, s), 9.56 (1H, s), 9.49 (1H, s), 8.43 + + − [4-(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine (1H, s), 8.20 (1H, d, J = 3.9Hz), 7.83 (2H, d, J = 8.7 Hz), 7.59 (2H, d, J = 8.7 Hz), 7.53 (1H, s),7.33-7.28 (2H, m), 7.02 (1H, d, J = 8.4 Hz), 1.52 (6H, s); purity 97.4%;MS (m/e): 1021 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N4- 1H NMR(DMSO-d6): d 10.72 (1H, s), 9.72 (1H, s), 8.20 (1H, d, J = + + +methyl-N2-[4- (oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 0.9 Hz), 8.11(1H, d, J = 5.7 Hz), 7.89 (4H, s), 7.38 (1H, d, J = 0.9 Hz), 7.07-6.97(2H, m), 6.87 (1H, d, J = 2.7 Hz), 3.54 (3H, s), 1.52 (6H, s); purity97.1%; MS (m/e): 461 (MH+). 1022 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N4- 1H NMR(DMSO-d6): d 10.70 (1H, s), 9.38 (1H, s), 8.05 (2H, d, J = + + −methyl-N2-[3- (N-methylamino)carbonylmethyleneoxyphenyl]- 5.4 Hz), 7.55(1H, m), 7.37 (1H, d, J = 8.4 Hz), 7.20 (1H, t, J = 7.8 Hz),2,4-pyrimidinediamine 7.03 (1H, d, J = 8.4 Hz), 6.97 (1H, dd, J = 8.4Hz, J = 2.1 Hz), 6.85 (1H, d, J = 2.1 Hz), 6.57 (1H, dd, J = 7.8 1023N4- (2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N4- 1H NMR(DMSO-d6): d 10.71 (1H, s), 9.55 (1H, s), 8.50 (1H, s), 8.37 + + −methyl-N2-[3- (oxazol-5-yl)phenyl]-2,4-pyrimidinediamine (1H, s), 8.08(1H, d, J = 5.7 Hz), 7.68 (1H, d, J = 8.1 Hz), 7.66 (1H, s), 7.43-7.34(2H, m), 7.05-6.97 (2H, m), 6.87 (1H, d, J = 2.4 Hz), 3.55 (3H, s), 1.51(6H, s); purity 95.6%; MS 1024 5-Fluoro-N4-methyl-N2-[4-(oxazol-2-yl)phenyl]-N4- (3-oxo- 1H NMR (DMSO-d6): d 9.71 (1H, s), 8.20(1H, d, J = 0.9 Hz), 8.10 + +2,2,4-trimethylbenz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine (1H, d, J = 6Hz), 7.90 (4H, s), 7.38 (1H, d, J = 0.6 Hz), 7.27 (1H, s), 7.09 (2H, s),3.59 (3H, s), 3.34 (3H, s), 1.52 (6H, s); purity 97.4%; MS (m/e): 475(MH+). 1025 5-Fluoro-N4-methyl-N2-[3- (oxazol-2-yl)phenyl]-N4- (3-oxo-1H NMR (DMSO-d6): d 9.65 (1H, s), 8.72 (1H, d, J = 1.8 Hz), 8.27 + +2,2,4-trimethylbenz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine (1H, d, J =0.6 Hz), 8.08 (1H, d, J = 6 Hz), 7.83-7.79 (1H, m), 7.60 (1H, d, J = 7.2Hz), 7.47 (1H, d, J = 7.8 Hz), 7.43 (1H, d, J = 0.9 Hz), 7.28 (1H, s),7.07 (2H, s), 3.62 (3H, s), 3.35 1026 5-Fluoro-N4-methyl-N2-[4-(oxazol-5-yl)phenyl]-N4- (2,2,4- 1H NMR (DMSO-d6): d 9.60 (1H, s), 8.44(1H, s), 8.07 (1H, d, J = 6 + −trimethyl-3-oxo-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine Hz), 7.88(2H, d, J = 8.4 Hz), 7.65 (2H, d, J = 8.7 Hz), 7.57 (1H, s), 7.27 (1H,s), 7.08 (2H, s), 3.58 (3H, s), 3.34 (3H, s), 1.52 (6H, s); purity98.61%; MS (m/e): 475 (MH+). 1027 N2-(3-Chloro-4-cyclopentyloxy-5-methylphenyl)-N4- (2,2- 1H NMR (DMSO-d6): d11.18 (1H, s), 9.38 (1H, s), 9.35 (1H, s), 8.22 + −dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4- (1H, d, J = 3.6Hz), 7.74 (1H, d, J = 2.4 Hz), 7.61 (1H, d, J = 8.7 Hz),pyrimidinediamine 7.46 (1H, d, J = 8.4 Hz), 7.41 (1H, d, J = 2.7 Hz),4.67 (1H, m), 2.26 (3H, s), 2.00-1.60 (8H, m), 1.53 (6H, s) 1028 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 11.18 (1H, s), 9.60 (1H, s), 9.37 (1H, s), 8.38 + + −N2-[3- (oxazol-2-yl)phenyl]-2,4-pyrimidinediamine (1H, s), 8.27 (2H, m),7.93 (1H, d, J = 8.4 Hz), 7.71 (1H, d, J = 8.7 Hz), 7.60 (1H, d, J = 8.1Hz), 7.44-7.34 (3H, m), 1.53 (6H, s); purity 95%; MS (m/e): 448 (MH+).1029 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1HNMR (DMSO-d6): d 11.17 (1H, s), 9.45 (1H, s), 9.31 (1H, s), 8.54 + + −N2-[3- (oxazol-4-yl)phenyl]-2,4-pyrimidinediamine (2H, dd, J = 9.9 Hz, J= 0.9 Hz), 8.24 (1H, d, J = 3.6 Hz), 8.10 (1H, s), 7.78-7.72 (2H, m),7.42-7.29 (3H, m), 1.52 (6H, s); purity 96.4%; MS (m/e): 448 (MH+). 10305-Fluoro-N4-methyl-N2-[3- (oxazol-4-yl)phenyl]-N4- (3-oxo- 1H NMR(DMSO-d6): d 9.47 (1H, s), 8.59 (1H, s), 8.51 (1H, s), 8.41 + +2,2,4-trimethylbenz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine (1H, s), 8.05(1H, d, J = 5.4 Hz), 7.66 (1H, d, J = 7.5 Hz), 7.41-7.32 (2H, m), 7.27(1H, s), 7.07 (2H, s), 3.60 (3H, s), 3.35 (3H, s), 1.51 (6H, s); purity97.4%; MS (m/e): 475 (MH+). 1031 N2-(3,5-Dimethyl-4-methoxyphenyl)-5-fluoro-N4-methyl-N4- (3- 1H NMR(DMSO-d6): d 9.11 (1H, s), 8.00 (1H, J = 5.7 Hz), 7.42 (2H, + −oxo-2,2,4-trimethyl-benz[1,4]oxazin-6-yl)-2,4- s), 7.24 (1H, s), 7.05(2H, s), 3.68 (3H, s), 3.55 (3H, s), 3.33 (3H, s), pyrimidinediamine2.25 (6H, s), 1.51 (6H, s); purity 97.84%; MS (m/e): 466 (M). 1032 N2-(3-Chloro-4-cyclopentyloxy-5-methylphenyl)-5-fluoro-N4- 1H NMR(DMSO-d6): d 9.49 (1H, s), 8.07 (1H, dd, J = 6 Hz, J = 1.5 − −methyl-N4- (3-oxo-2,2,4-trimethyl-benz[1,4]oxazin-6-yl)-2,4- Hz), 7.81(1H, d, J = 2.7 Hz), 7.47 (1H, d, J = 2.4 Hz), 7.27 (1H, s),pyrimidinediamine 7.07 (2H, s), 4.69 (1H, m), 3.61 (3H, s), 3.33 (3H,s), 2.29 (3H, s), 2.0- 1.6 (8H, m), 1.51 (6H, s); purity 96.15%; 1033N2- (3,5-Dimethyl-4-methoxyphenyl)-5-fluoro-N4- (3-oxo-2,2,4- 1H NMR(DMSO-d6): d 9.49 (1H, d, J = 0.9 Hz), 9.15 (1H, s), 8.21 + + +trimethyl-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine (1H, d, J = 3.6Hz), 7.81 (1H, d, J = 8.7 Hz), 7.45 (1H, d, J = 8.4 Hz), 7.35 (2H, s),3.69 (3H, s), 3.43 (3H, s), 2.23 (6H, s), 1.54 (6H, s); purity 98.82%;MS (m/e): 453 (M). 1034 N2-(3-Chloro-4-cyclopentyloxy-5-methylphenyl)-5-fluoro-N4- 1H NMR(DMSO-d6): d 9.63 (1H, s), 9.40 (1H, s), 8.26 (1H, d, J = 3.6 + −(3-oxo-2,2,4-trimethyl-benz[1,4]oxazin-6-yl)-2,4- Hz), 7.78 (1H, d, J =2.4 Hz), 7.72 (1H, d, J = 8.4 Hz), 7.48 (1H, d, J = pyrimidinediamine8.4 Hz), 7.41 (1H, d, J = 2.4 Hz), 4.68 (1H, m), 3.41 (3H, s), 2.26 (3H,s), 1.95-1.60 (8H, m), 1.54 (6H, s); 1035 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 11.23 (1H, s), 9.70 (1H, s), 9.53 (1H, s), 8.27 − N2-[4-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine (1H, d, J = 3.6 Hz), 8.20(1H, d, J = 0.9 Hz), 7.90 (2H, d, J = 9.3 Hz), 8.86 (2H, d, J = 9.5 Hz),7.55 (1H, d, J = 8.4 Hz), 7.51 (1H, d, J = 8.4 Hz), 7.37 (1H, J = 0.9Hz), 1.56 (6H, s 1036 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 10.65 (1H, s), 9.41 (1H, d, J = 1.2 Hz), 9.32 + + + [3-(oxazol-4-yl)phenyl]-2,4-pyrimidinediamine (1H, s), 8.50 (1H, d, J = 0.6Hz), 8.47 (1H, s), 8.17 (1H, d, J = 3.9 Hz), 8.08 (1H, s), 7.78 (1H, d,J = 8.7 Hz), 7.43 (1H, dd, J = 8.7 Hz, J = 2.4 Hz), 7.39-7.27 (3H, m),6.88 (1H, d, J 1037 N2-[3-Chloro-5-methyl-4- (N- 1H NMR (DMSO-d6): d11.19 (1H, s), 9.43 (2H, s), 8.24 (1H, d, J = + −methylamino)carbonylmethyleneoxyphenyl]-N4- (2,2-dimethyl- 7.8 Hz), 8.18(1H, d, J = 4.5 Hz), 7.78 (1H, d, J = 2.4 Hz), 7.60 (1H, d,3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4- J = 8.4 Hz), 7.47 (1H,d, J = 8.4 Hz), 7.43 (1H, d, J = 2.4 Hz), 4.32 pyrimidinediamine (2H,s), 2.79 (3H, d, J = 4.8 Hz), 2.29 (3H 1038 N2-(3,5-Dimethyl-4-ethoxycarbonylmethyleneoxyphenyl)-N4- 1H NMR (DMSO-d6):d 11.18 (1H, s), 9.26 (1H, s), 9.16 (1H, s), 8.19 + −(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4- (1H, d, J= 3.3 Hz), 7.68 (1H, d, J = 8.4 Hz), 7.46 (1H, d, J = 8.4 Hz),pyrimidinediamine 7.33 (2H, s), 4.49 (2H, s), 4.28 (2H, q, J = 7.2 Hz),2.23 (6H, s), 1.52 (6H, s), 1.33 (3H, t, J = 7.2 Hz); pur 1039 N2-(3-Chloro-4-isopropoxy-5-methylphenyl)-N4- (2,2-dimethyl- 1H NMR(DMSO-d6): d 10.72 (1H, s), 9.68 (1H, s), 9.44 (1 H, s), 8.20 + +3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine (1H, d, J= 3.6 Hz), 7.70 (1H, d, J = 2.1 Hz), 7.42 (1H, d, J = 2.4 Hz), 7.35 (1H,dd, J = 8.7 Hz, J = 2.4 Hz), 7.24 (1H, d, J = 2.4 Hz), 6.98 (1H, d, J =8.4 Hz), 4.36 (1H, quint, J= 1040 N2-(3-Chloro-4-isopropoxy-5-methylphenyl)-N4- (2,2-dimethyl- 1H NMR(DMSO-d6): d 11.17 (1H, s), 9.37 (1H, s), 9.35 (1H, s), 8.22 − +3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4- (1H, d, J = 3.0 Hz),7.74 (1H, d, J = 2.7 Hz), 7.61 (1H, d, J = 8.7 Hz), pyrimidinediamine7.45 (1H, d, J = 8.7 Hz), 7.41 (1H, d, J = 2.7 Hz), 4.36 (1H, quint, J =6.0 Hz), 2.25 (3H, s), 1.52 (6H, s), 1. 1041 N2-[3,5-Dimethyl-4- (N- 1HNMR (DMSO-d6): d 11.18 (1H, s), 9.28 (1H, s), 9.18 (1H, s), 8.19 + + +methylamino)carbonylmethyleneoxyphenyl]-N4- (2,2-dimethyl- (2H, d, J =3.6 Hz), 7.68 (1H, d, J = 8.4 Hz), 7.45 (1H, d, J = 8.7 Hz),3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4- 7.34 (2H, s), 4.22 (2H,s), 2.79 (3H, d, J = 4.5 Hz), 2.23 (6H, s), 1.52 pyrimidinediamine (6H,s); purity 98%; MS (m/e): 496 (MH 1042 N2-(3-Chloro-4-ethoxycarbonylmethyleneoxy-5-methylphenyl)- 1H NMR(DMSO-d6): d 11.19 (1H, s), 9.42 (2H, s), 8.23 (1H, d, J = − − N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 3.6 Hz), 7.76(1H, d, J = 2.4 Hz), 7.60 (1H, d, J = 8.4 Hz), 7.47 (1H, d,2,4-pyrimidinediamine J = 8.4 Hz), 7.42 (1H, d, J = 2.1 Hz), 4.60 (2H,s), 4.27 (2H, q, J = 7.2 Hz), 2.29 (3H, s), 1.52 (6H, s), 1.33 ( 1043N2-[3-Chloro-4-[N- (2,3- 1H NMR (DMSO-d6): d 11.17 (1H, s), 9.42 (1H,s), 9.40 (1H, s), 8.23 + + −dihydroxypropyl)amino]carbonylmethyleneoxy-5- (1H, d, J = 3.6 Hz), 7.98(1H, t, J = 5.7 Hz), 7.78 (1H, d, J = 2.7 Hz), methylphenyl]-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6- 7.61 (1H, d, J = 8.7 Hz),7.47 (1H, d, J = 8.4 Hz), 7.34 (1H, d, J = 1.8yl)-5-fluoro-2,4-pyrimidinediamine Hz), 4.94 (1H, broad s), 4.67 (1H,broa 1044 N2-[3,5-Dimethyl-4- (N- 1H NMR (DMSO-d6): d 11.18 (1H, s),9.27 (1H, s), 9.17 (1H, s), 8.19 − − −cyclopentylamino)carbonylmethyleneoxyphenyl]-N4- (2,2- (1H, d, J = 3.6Hz), 8.03 (1H, d, J = 7.8 Hz), 7.67 (1H, d, J = 8.7 Hz),dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4- 7.45 (1H, d, J= 8.7 Hz), 7.34 (2H, s), 4.23 (1H, m), 4.21 (2H, s), 2.23pyrimidinediamine (6H, s), 1.91 (2H, m), 1.76 (2H, m), 1. 1045 N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 12.12 (1H, s), 9.95 (1H, s), 9.58 (1H, s), 8.26 + + − [3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- (1H, d, J = 3.6 Hz),8.06 (1H, d, J = 4.2 Hz), 7.65 (1H, d, J = 2.1 Hz), pyrimidinediamineHydrogen Chloride Salt 7.61 (1H, d, J = 2.4 Hz), 7.41 (1H, s), 7.35 (1H,d, J = 8.7 Hz), 7.30 (1H, d, J = 9.0 Hz), 7.21 (1H, t, J = 7.8 1046 N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 12.05 (1H, s), 9.81 (1H, s), 9.38 (1H, s), 8.24 + + − [3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- (1H, d, J = 3.6 Hz),8.04 (1H, d, J = 4.2 Hz), 7.66 (1H, dd, J = 10.5 Hz, pyrimidinediamineMethanesulfonic Acid Salt J = 1.5 Hz), 7.51 (1H, d, J = 1.8 Hz), 7.43(1H, s), 7.36-7.29 (2H, m), 7.19 (1H, t, J = 7.8 Hz), 6.59 (1H, d, 1047N4- (2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 10.74 (1H, s), 10.11 (1H, s), 9.82 (1H, s), − + −(indazol-6-yl)-2,4-pyrimidinediamine Methanesulfonic Acid Salt 8.26 (1H,d, J = 4.5 Hz), 8.05 (1H, s), 7.88 (1H, s), 7.71 (1H, d, J = 8.4 Hz),7.45 (1H, dd, J = 9.0 Hz, J = 2.7 Hz), 7.31 (1H, dd, J = 8.7 Hz, J = 1.5Hz), 7.24 (1H, d, J = 2.4 Hz), 6.97 1048 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 10.73 (1H, s), 9.282 (1H, s), 9.60 (1H, s), + + −(indazol-6-yl)-2,4-pyrimidinediamine Hydrogen Chloride Salt 8.24 (1H, d,J = 4.2 Hz), 8.02 (2H, s), 7.67 (1H, d, J = 8.4 Hz), 7.47 (1H, d, J =8.7 Hz), 7.36-7.33 (2H, m), 6.98 (1H, d, J = 8.7 Hz), 1.49 (6H, s);purity 99.3%; MS (m/e): 420 (MH+). 1049 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2- (1- 1H NMR(DMSO-d6): d 11.21 (1H, s), 9.56 (1H, s), 9.40 (1H, s), 8.29 + + −ethylindazol-6-yl)-5-fluoro-2,4-pyrimidinediamine (1H, d, J = 3.6 Hz),8.11 (1H, s), 7.96 (1H, s), 7.71 (1H, d, J = 7.2 Hz), 7.64 (1H, d, J =9.0 Hz), 7.46 (1H, d, J = 8.4 Hz), 7.36 (1H, dd, J = 8.7 Hz, J = 1.5Hz), 4.25 (2H, q, J = 7. 1050 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2- (1- 1H NMR(DMSO-d6): d 11.22 (1H, s), 9.56 (1H, s), 9.41 (1H, s), 8.29 + + −isopropylindazol-6-yl)-5-fluoro-2,4-pyrimidinediamine (1H, d, J = 3.3Hz), 8.15 (1H, s), 7.96 (1H, s), 7.70 (1H, d, J = 8.4 Hz), 7.63 (1H, d,J = 8.4 Hz), 7.46 (1H, d, J = 8.7 Hz), 7.35 (1H, dd, J = 8.7 Hz, J = 1.2Hz), 4.63 (1H, quint, J 1051 2-Chloro-N4-(3,4-dihydro-2,2-dimethyl-4H-5-pyrid[1,4]oxazin- 1H NMR (DMSO-d6): d9.84 (1H, s), 8.35 (1H, d, J = 3.3 Hz), 7.09 − −6-yl)-5-fluoro-4-pyrimidineamine (1H, d, J = 8.1 Hz), 7.06 (1H, d, J =8.1 Hz), 6.79 (1H, s), 3.23 (2H, s), 1.36 (6H, s); purity 96.73%; MS(m/e): 310 (MH+). 1052 N4-(3,4-Dihydro-2,2-dimethyl-4H-5-pyrid[1,4]oxazin-6-yl)-5- 1H NMR(DMSO-d6): d 9.50 (1H, s), 8.94 (1H, s), 8.21 (1H, d, J = 3.6 + + +fluoro-N2- (1-methylindazol-6-yl)-2,4-pyrimidinediamine Hz), 8.17 (1H,s), 7.93 (1H, s), 7.63 (1H, d, J = 8.7 Hz), 7.35 (1H, d, J = 1.5 Hz),7.30 (1H, d, J = 7.8 Hz), 7.01 (1H, d, J = 8.4 Hz), 6.72 (1H, s), 3.92(3H, s), 3.24 (2H, d, J = 2. 1053 N4-(3,4-Dihydro-2,2-dimethyl-4H-5-pyrid[1,4]oxazin-6-yl)-5- 1H NMR(DMSO-d6): d 9.29 (1H, s), 8.83 (1H, s), 8.15 (1H, d, J = 3.6 + + −fluoro-N2-[3- (N-methylamino)carbonylmethyleneoxyphenyl]- Hz), 8.03 (1H,m), 7.47 (1H, t, J = 2.1 Hz), 7.40 (1H, d, J = 7.5 Hz),2,4-pyrimidinediamine 7.34 (1H, d, J = 6.9 Hz), 7.20 (1H, t, J = 8.4Hz), 7.02 (1H, d, J = 8.1 Hz), 6.67 (1H, s), 6.56 (1H, dd, J = 7.8 1054N2-[3-Chloro-4- (N-methylamino)carbonylphenyl]-N4- (2,2- 1H NMR(DMSO-d6): d 11.19 (1H, s), 9.70 (1H, s), 9.52 (1H, s), 8.28 + + −dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4- (1H, d, J = 2.4Hz), 8.21 (1H, d, J = 5.1 Hz), 7.97 (1H, s), 7.62-7.57 pyrimidinediamine(2H, m), 7.50 (1H, d, J = 9.0 Hz), 7.34 (1H, d, J = 8.4 Hz), 2.81 (3H,d, J = 3.6 Hz), 1.53 (6H, s); purity 99.5% 1055 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2- (3,4- 1H NMR(DMSO-d6): d 11.12 (1H, s), 9.25 (1H, s), 9.12 (1H, s), 8.17 + + −ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine (1H, d, J = 3.3 Hz),7.64 (1H, d, J = 8.4 Hz), 7.43 (1H, d, J = 8.4 Hz), 7.35 (1H, d, J = 2.4Hz), 7.10 (1H, dd, J = 9.0 Hz, J = 2.4 Hz), 6.76 (1H, d, J = 9.0 Hz),4.26 (4H, m), 1.53 (6H, 1056 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 11.23 (1H, s), 9.88 (1H, s), 9.28 (1H, s), 8.33 + + −N2-[1-methylindazol-6-yl]-2,4-pyrimidinediamine Hydrogen (1H, d, J = 3.6Hz), 8.02 (1H, s), 7.98 (1H, s), 7.66 (2H, t, J = 8.4 Hz). Chloride Salt7.45 (1H, d, J = 8.4 Hz), 7.31 (1H, dd, J = 8.4 Hz, J = 1.5 Hz), 3.93(3H, s), 1.53 (6H, s); purity 100%; MS 1057 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 11.23 (1H, s), 9.81 (2H, s), 8.32 (1H, d, J = + + −N2-[1-methylindazol-6-yl]-2,4-pyrimidinediamine p- 3.9 Hz), 8.02 (1H,s), 7.98 (1H, s), 7.67 (2H, t, J = 8.7 Hz), 7.55 (2H, d, ToluenesulfonicAcid Salt J = 7.8 Hz), 7.44 (1H, d, J = 8.4 Hz), 7.31 (1H, dd, J = 8.4Hz, J = 0.9 Hz), 7.19 (2H, d, J = 8.4 Hz), 3.94 (3 1058 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- 1H NMR(DMSO-d6): d 11.22 (1H, s), 9.76 (1H, s), 9.72 (1H, s), 8.31 + + −N2-[1-methylindazol-6-yl]-2,4-pyrimidinediamine (1H, d, J = 3.3 Hz),8.04 (1H, s), 7.97 (1H, s), 7.67 (2H, d, J = 8.4 Hz), MethanesulfonicAcid Salt 7.45 (1H, d, J = 8.1 Hz), 3.32 (1H, d, J = 8.4 Hz), 3.93 (3H,s), 2.41 (3H, s), 1.53 (6H, s); purity 99%; MS 1059 N2-(3,5-Dimethyl-4-methoxyphenyl)-5-fluoro-N4- (3-oxo- 1H NMR (DMSO-d6): d2.13 (s, 6H), 3.58 (s, 3H), 4.62 (s, 2H), 7.22 (s, +2H,4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 2H), 7.33 (d, J =9.0 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 3.6 Hz, 1H), 9.01(s, 1H), 9.15 (s, 1H), 11.13 (s, 1H); 19F NMR (282 MHz, DMSO-d6): d -163.82; LCMS: ret. time: 10.29 min.; purity: 97.75%; MS (m/e): 411.18(MH+) 1060 N4- (2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-¹H NMR (CDCl3): d 1.45 (s, 6H), 2.13 (s, 3H), 6.78 (m, 3H), 6.90 (d, +(3-hydroxy-2-methylphenyl)-2,4-pyrimidinediamine J = 7.5 Hz, 1H), 7.04(t, J = 8.1 Hz, 1H), 7.27 (s, 1H), 7.74 (d, J = 5.1 Hz, 1H), 7.91 (s,1H), 9.09 (s, 1H), 10.86 (s, 1H); 19F NMR (282 MHz, CDCl3): d - 162.90;LCMS: ret. time: 8.06 min 1061 5-Fluoro-N2-(3-methoxy-2-methylphenyl)-N4- (3-oxo-2H,4H-5- ¹H NMR (DMSO-d6): d 1.99(s, 3H), 3.79 (s, 3H), 4.60 (s, 2H), 6.54 (d, +pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine J = 7.8 Hz, 1H), 6.78 (d, J= 8.1 Hz, 1H), 6.98 (dd, J = 2.4 and 8.1 Hz, 1H), 7.12 (t, J = 8.4 Hz,1H), 7.44 (d, J = 8.7 Hz, 1H), 8.03 (d, J = 3.9 Hz, 1H), 8.73 (s, 1H),9.23 (s, 1H), 11.08 1062 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- ¹H NMR(CDCl3): d 1.49 (s, 6H), 2.12 (s, 3H), 3.95 (s, 3H), 6.71 (dd, +(3-methoxy-2-methylphenyl)-2,4-pyrimidinediamine J = 2.1 and 8.4 Hz,1H), 6.79 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 6.98 (d, J =8.4 Hz, 1H), 7.26 (m, 3H), 7.66 (d, J = 4.2 Hz, 1H), 7.93 (s, 1H), 11.04(s, 1H); 19F NMR (282 MHz, 1063 5-Fluoro-N2-(3-hydroxy-2-methylphenyl)-N4- (3-oxo-2H,4H-5- ¹H NMR (CDCl3): d 2.02(s, 3H), 4.48 (s, 2H), 6.72 (m, 2H), 6.82 (m, +pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 1H), 6.96 (t, J = 8.1 Hz,1H), 7.25 (m, 1H), 7.79 (d, J = 4.8 Hz, 1H); LCMS: ret. time: 7.10 min.;purity: 77.55%; MS (m/e): 383.14 (MH+). 1064 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- ¹H NMR(CDCl3): d 1.41 (s, 6H), 2.04 (s, 3H), 6.61 (t, J = 4.5 Hz, 1H), + N2-(3-hydroxy-2-methylphenyl)-2,4-pyrimidinediamine 6.94 (m, 3H), 7.58 (d,J = 8.7 Hz, 1H), 7.77 (d, J = 3.9 Hz, 1H); 19F NMR (282 MHz, CDCl3): d -165.40; LCMS: ret. time: 7.83 min.; purity: 99.01%; MS (m/e): 411.19(MH+). 1065 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- ¹H NMR(CDCl3): d 1.57 (s, 6H), 2.19 (s, 3H), 3.88 (s, 3H), 6.79 (dd, + N2-(3-methoxy-2-methylphenyl)-2,4-pyrimidinediamine J = 2.1 and 7.2 Hz,1H), 7.05 (d, J = 8.7 Hz, 1H), 7.17 (m, 2H), 7.70 (d, J = 8.7 Hz, 1H),7.85 (d, J = 3.6 Hz, 1H); 19F NMR (282 MHz, CDCl3): d - 161.49; LCMS:ret. time: 10.92 min.; purit 1066 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- ¹H NMR(CDCl3): d 1.49 (s, 6H), 2.26 (s, 3H), 3.80 (s, 3H), 4.84 (s, +[3-methoxycarbonylmethyleneoxy-2-methylphenyl]-2,4- 2H), 6.69 (dd, J =2.4 and 8.4 Hz, 1H), 6.82 (d, J = 8.7 Hz, 1H), 6.86 (d,pyrimidinediamine J = 8.1 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 7.19 (t, J= 8.1 Hz, 1H), 7.26 (s, 1H), 7.46 (s, 1H), 7.72 (s, 1H), 7.79 1067 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- ¹H NMR(CDCl3): d 1.50 (s, 6H), 2.25 (s, 3H), 2.93 (d, J = 4.8 Hz, 3H), +[2-methyl-3- (N-methylamino)carbonylmethyleneoxyphenyl]- 4.57 (s, 2H),6.82 (m, 4H), 6.97 (t, J = 8.1 Hz, 1H), 7.19 (m, 2H), 7.402,4-pyrimidinediamine (s, 1H), 7.54 (s, 1H), 7.81 (d, J = 4.2 Hz, 1H);LCMS: ret. time: 8.08 min.; purity: 99.78%; MS (m/e): 481.21 (MH 10685-Fluoro-N2-[2-methyl-3- (N- ¹H NMR (DMSO-d6): d 2.08 (s, 3H), 2.66 (d,J = 4.5 Hz, 3H), 4.46 (s, + methylamino)carbonylmethyleneoxyphenyl]-N4-(3-oxo-2H,4H- 2H), 4.58 (s, 2H), 6.65 (dd, J = 1.8 and 7.2 Hz, 1H), 7.04(m, 2H), 7.15 5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine (d, J = 8.7Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.84 (d, J = 4.2 Hz, 1H), 8.01 (d, J= 3.6 Hz, 1H), 8.54 (s, 1H), 8.96 ( 1069 N2-(3,5-Dimethyl-4-hydroxyphenyl)-5-fluoro-N4- (3-oxo-2H,4H- ¹H NMR(DMSO-d6): d 2.09 (s, 6H), 4.62 (s, 2H), 7.05 (s, 2H), 7.28 (d, +5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine J = 8.4 Hz, 1H), 7.55 (d,J = 8.1 Hz, 1H), 7.89 (br, 1H), 8.07 (d, J = 3.6 Hz, 1H), 9.03 (s, 1H),9.36 (s, 1H), 11.15 (s, 1H); 19F NMR (282 MHz, DMSO-d6): d - 163.98;LCMS: ret. time: 7.9 1070 N2-[3-(4-Ethoxycarbonylpiperazino)phenyl]-5-fluoro-N4- (3- ¹H NMR (CDCl3): d1.14 (t, J = 7.2 Hz, 3H), 3.00 (t, J = 5.1 Hz, 4H), +oxo-2H,4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 3.46 (t, J =5.1 Hz, 4H), 4.00 (q, J = 7.2 Hz, 2H), 4.47 (s, 2H), 6.55 (dd, J = 1.8and 8.4 Hz, 1H), 6.90 (dd, J = 1.2 and 7.8 Hz, 1H), 6.98 (t, J = 2.1 Hz,1H), 7.04 (d, J = 8.7 Hz, 1H), 7.08 1071 N2-[3-(4-Acetylpiperazino)phenyl]-5-fluoro-N4- (3-oxo-2H,4H-5- ¹H NMR (CDCl3):d 2.01 (s, 3H), 3.02 (t, J = 5.1 Hz, 2H), 3.08 (t, J = 5.1 +pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine Hz, 2H), 3.50 (t, J = 5.1Hz, 2H), 3.58 (t, J = 5.4 Hz, 2H), 4.50 (s, 2H), 6.66 (dd, J = 2.4 and8.4 Hz, 1H), 6.87 (t, J = 2.4 Hz, 1H), 6.92 (ddd, J = 0.9, 2.1 and 7.8Hz, 1H), 6.98 (d, J 1072 N2-[4-(4-Ethoxycarbonylpiperazino)phenyl]-5-fluoro-N4- (3- ¹H NMR (DMSO-d6): d1.20 (t, J = 7.2 Hz, 3H), 2.99 (t, J = 5.1 Hz, 4H), +oxo-2H,4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 3.49 (t, J =5.1 Hz, 4H), 4.05 (q, J = 7.2 Hz, 2H), 4.63 (s, 2H), 6.83 (d, J = 9.3Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 9.0 Hz, 2H), 7.56 (d, J= 8.4 Hz, 1H), 8.06 (d, J = 3.6 Hz, 1 1073 5-Fluoro-N2-(3-morpholinophenyl)-N4- (3-oxo-2H,4H-5- ¹H NMR (DMSO-d6): d 2.98 (t, J= 5.1 Hz, 4H), 3.69 (t, J = 5.1 Hz, 4H), +pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 4.62 (s, 2H), 6.50 (d, J =7.2 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 7.17 (d, J = 7.2 Hz, 1H), 7.18(s, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 8.11 (d, J= 3.6 Hz, 1H), 9.09 (s 1074 5-Fluoro-N2-[3-(4-methylpiperazino)phenyl]-N4- (3-oxo-2H,4H- ¹H NMR (DMSO-d6): d 2.85(s, 3H), 2.90 (m, 2H), 3.23 (m, 4H), 3.67 +5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine (m, 2H), 4.63 (s, 2H),6.57 (dd, J = 2.1 and 8.4 Hz, 1H), 7.08 (t, J = 8.1 Hz, 1H), 7.20 (s,1H), 7.28 (m, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H),8.11 (d, J = 3.3 Hz, 1H), 9.1 1075 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-[3- (4- ¹H NMR(DMSO-d6): d 1.19 (t, J = 7.2 Hz, 3H), 1.42 (s, 6H), 3.00 (t, +ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4- 4H), 3.45 (t, J = 4.8 Hz,4H), 4.04 (q, J = 7.2 Hz, 2H), 6.51 (d, J = 9.3 pyrimidinediamine Hz,1H), 7.03 (t, J = 8.1 Hz, 1H), 7.18 (s, 1H), 7.20 (d, J = 6.6 Hz, 1H),7.34 (t, J = 8.4 Hz, 1H), 7.59 (d, J = 8.7 Hz 1076 N2-[3-(4-Acetylpiperazino)phenyl]-N4- (2,2-dimethyl-3-oxo-4H- ¹H NMR (CDCl3):d 1.46 (s, 6H), 2.06 (s, 3H), 3.08 (t, J = 5.1 Hz, 2H), +5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 3.13 (t, J = 5.1Hz, 2H), 3.54 (t, J = 5.1 Hz, 2H), 3.65 (t, J = 5.1 Hz, 2H), 6.67 (dd, J= 2.4 and 8.4 Hz, 1H), 6.94 (t, J = 2.1 Hz, 1H), 7.01 (ddd, J = 0.9, 1.8and 7.8 Hz, 1H), 7.05 (d, J 1077 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-N2-[4- (4- ¹H NMR (DMSO-d6): d 1.20 (t, J = 7.2 Hz,3H), 1.43 (s, 6H), 3.03 (t, +ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4- 4H), 3.50 (t, 4H), 4.05(q, J = 7.2 Hz, 2H), 6.88 (d, J = 9.3 Hz, 2H), 7.38 pyrimidinediamine(d, J = 8.4 Hz, 1H), 7.45 (d, J = 9.9 Hz, 2H), 7.51 (d, J = 8.7 Hz, 1H),8.09 (d, J = 3.9 Hz, 1H), 9.24 (s, 1H), 9.44 1078 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- ¹H NMR(DMSO-d6): d 1.42 (s, 6H), 3.00 (t, J = 4.8 Hz, 4H), 3.69 (t, J = + N2-(3-morpholinophenyl)-2,4-pyrimidinediamine 4.8 Hz, 4H), 6.51 (dd, J =7.5 Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H), 7.16 (s, 1H), 7.17 (d, J = 8.4Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 8.12 (d, J= 3.6 Hz, 1H), 9.17 ( 1079 N4- (2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- ¹H NMR (DMSO-d6): d 1.39 (s, 6H), 2.08 (s,3H), 2.65 (d, J = 4.8 Hz, + N2-[2-methyl-3- (N- 3H), 4.45 (s, 2H), 6.64(dd, J = 2.7 and 6.6 Hz, 1H), 7.04 (m, 2H), 7.15methylamino)carbonylmethyleneoxyphenyl]-2,4- (d, J = 8.4 Hz, 1H), 7.48(d, J = 8.4 Hz, 1H), 7.84 (d, J = 3.9 Hz, 1H), pyrimidinediamine 8.01(d, J = 3.6 Hz, 1H), 8.56 (s, 1H), 8.98 ( 1080 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid [1,4]oxazin-6-yl)-5-fluoro- ¹H NMR(CDCl3): d 1.42 (s, 6H), 2.77 (s, 3H), 3.20 (m, 4H), 3.30 (m, + N2-[3-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine 4H), 6.61 (d, J = 6.9Hz, 1H), 6.92 (t, J = 2.4 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 7.13 (m,2H), 7.70 (d, J = 8.7 Hz, 1H), 7.81 (d, J = 4.2 Hz, 1H); 19F NMR (282MHz, CDCl3): d - 162.81; LCMS 1081 (S)-N2-(3-Chloro-4-methoxyphenyl)-5-fluoro-N4- (2-methyl-3- ¹H NMR (DMSO-d6): d1.45 (d, J = 6.6 Hz, 3H), 3.77 (s, 3H), 4.73 (q, + +oxo-2H,4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine J = 6.6 Hz,1H), 6.99 (d, J = 9.0 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.48 (m, 2H),7.80 (d, J = 2.1 Hz, 1H), 8.11 (d, J = 3.6 Hz, 1H), 9.21 (s, 1H), 9.26(s, 1H), 11.09 (s, 1H); 19F NMR (282M 1082 (S)-5-Fluoro-N4-(2-methyl-3-oxo-2H,4H-5-pyrid[1,4]oxazin-6- ¹H NMR (DMSO-d6): d 1.45 (d,J = 6.9 Hz, 3H), 3.59 (s, 3H), 3.65 (s, + + yl)-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 6H), 4.72 (q, J = 6.6 Hz,1H), 7.02 (s, 2H), 7.32 (d, J = 8.7 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H),8.11 (d, J = 3.3 Hz, 1H), 9.10 (s, 1H), 9.17 (s, 1H), 11.07 (s, 1H); 19FNMR (282 MHz, DMSO-d6 1083 N2,N4-Bis(3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4- ¹H NMR (DMSO-d6): d4.46 (s, 2H), 4.52 (s, 2H), 6.76 (d, J = 9.3 Hz, + + + pyrimidinediamine1H), 6.86 (d, J = 8.7 Hz, 1H), 7.18 (m, 2H), 7.23 (d, J = 2.4 Hz, 1H),7.33 (dd, J = 2.4 and 8.7 Hz, 1H), 8.00 (d, J = 3.6 Hz, 1H), 8.94 (s,1H), 9.29 (s, 1H), 10.58 (s, 1H), 10.63 (s, 1H); 1 1084 (S)-N2-(3,5-Dimethylphenyl)-5-fluoro-N4- (2-methyl-3-oxo- ¹H NMR (DMSO-d6): d1.44 (d, J = 6.9 Hz, 3H), 2.17 (s, 6H), 4.72 (q, − +2H,4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine J = 6.9 Hz, 1H),6.52 (s, 1H), 7.22 (s, 2H), 7.35 (d, J = 8.7 Hz, 1H), 7.89 (d, J = 8.4Hz, 1H), 8.11 (d, J = 3.6 Hz, 1H), 9.09 (s, 1H), 9.16 (s, 1H), 11.08 (s,1H); 19F NMR (282 MHz, DMSO-d6 1085 N2-[3-(4-Acetylpiperazino)phenyl]-N4-cyclobutyl-5-fluoro-2,4- ¹H NMR (CDCl3):d 1.82 (m, 2H), 2.03 (m, 2H), 2.15 (s, 3H), 2.46 (m, + −pyrimidinediamine 2H), 3.20 (m, 4H), 3.63 (t, J = 5.1 Hz, 2H), 3.78 (t,J = 5.1 Hz, 2H), 4.58 (m, J = 8.1 Hz, 1H), 5.26 (d, J = 6.6 Hz, 1H),6.58 (dd, J = 1.8 and 8.1 Hz, 1H), 7.01 (dd, J = 1.5 and 7.8 Hz, 1H),1086 N2- (5-tert-Butylpyrazol-3-yl)-5-fluoro-N4- (3-oxo-2H,4H-5- ¹H NMR(DMSO-d6): d 1.29 (s, 9H), 4.64 (s, 2H), 5.59 (s, 1H), 7.10 (d, + −pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 1H), 7.47 (d, J = 6.6 Hz,1H), 8.24 (d, 1H), 10.02 (s, 1H), 10.40 (s, 1H); 19F NMR (282 MHz,DMSO-d6): d - 162.59; LCMS: ret. time: 10.51 min.; purity: 78.44%; MS(m/e): 399.24 (MH+). 1087 N4-Cyclobutyl-N2-(3,5-dimethylphenyl)-5-fluoro-2,4- 1H NMR (CDCl3): d 1.78-1.87 (m, 2H),1.96-2.03 (m, 2H), 2.32 (s, + + − pyrimidinediamine 6H), 2.44-2.53 (m,2H), 4.56 (m, J = 7.8 Hz, 1H), 5.26 (d, J = 7.8 Hz, 1H), 6.67 (s, 1H),7.23 (s, 2H), 7.34 (br, NH, 1H), 7.72 (d, J = 2.7 Hz, 1H); 19F NMR (282MHz, CDCl3): d - 168.35; LCMS: 1088 N4-Cyclobutyl-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4- 1H NMR (CDCl3): d 1.71-1.86 (m, 2H),1.93-2.06 (m, 2H), 2.43-2.53 + + − pyrimidinediamine (m, 2H), 3.81 (s,6H), 4.60 (m, J = 7.8 Hz, 1H), 5.31 (d, 1H), 6.16 (t, J = 2.1 Hz, 1H),6.84 (d, J = 2.1 Hz, 2H), 7.57 (br, NH, 1H), 7.72 (d, J = 3.6 Hz, 1H);19F NMR (282 MHz, CDCl3): d - 167 1089 N4-Cyclobutyl-5-fluoro-N2-(3-methoxy-5- 1H NMR (CDCl3): d 1.75-2.04 (m, 4H), 2.43-2.53 (m, 2H),3.85 (s, + + − trifluoromethylphenyl)-2,4-pyrimidinediamine 3H), 4.58(m, J = 7.8 Hz, 1H), 5.32 (d, J = 6.6 Hz, 1H), 6.76 (s, 1H), 7.18 (t, J= 2.1 Hz, 1H), 7.52 (br, NH, 1H), 7.76 (s, 2H); 19F NMR (282 MHz,CDCl3): d - 167.20, −63.67; LCMS: ret. time: 1090 N4-(5-tert-Butyl-1H-pyrazol-3-yl)-5-fluoro-N2- (3- LCMS: ret. time: 11.58min.; purity: 90.45%; MS (m/e): 412.33 (MH+). + + −morpholinophenyl)-2,4-pyrimidinediamine 1091 N2-[3-(4-Acetylpiperazino)phenyl]-N4- (5-tert-butyl-1H-pyrazol- 1H NMR(CDCl3): d 1.20 (s, 9H), 2.04 (s, 3H), 3.06 (t, J = 5.4 Hz, 2H), + + −3-yl)-5-fluoro-2,4-pyrimidinediamine 3.11 (t, J = 5.1 Hz, 2H), 3.53 (t,J = 5.1 Hz, 2H), 3.63 (t, J = 5.1 Hz, 2H), 6.10 (s, 1H), 6.57 (m, 1H),6.96 (s, 1H), 7.13 (m, 2H), 7.82 (d, J = 3.9 Hz, 1H); LCMS: ret. time:8.84 min.; 1092 (S)-N2- (5-tert-Butyl-1H-pyrazol-3-yl)-5-fluoro-N4-(2-methyl-3- 1H NMR (DMSO-d6): d 1.30 (s, 9H), 1.47 (d, J = 6.6 Hz, 3H),4.74 (q, + + − oxo-2H,4H-5-pyrid[1,4]oxazin-6-yl)-2,4-pyrimidinediamineJ = 6.3 Hz, 1H), 5.60 (s, 1H), 7.09 (d, J = 9.0 Hz, 1H), 7.49 (d, J =8.4 Hz, 1H), 8.23 (d, J = 3.9 Hz, 1H), 10.02 (s, 1H), 10.39 (s, 1H); 19FNMR (282 MHz, DMSO-d6): d - 162.62; LCMS: ret. t 1093 N2-(3,5-Dimethyl-4-methoxyphenyl)-5-fluoro-[3- (N-2- 1H NMR (DMSO-d6): d2.16 (s, 6H), 3.61 (s, 4H), 3.64 (s, 3H), 6.98 + + − +imidazolin-2-yl)aminophenyl]-2,4-pyrimidinediamine (d, J = 11 Hz, 1H),7.00 (s, 1H), 7.23 (s, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.75 (d, J = 6.6Hz, 1H), 8.19 (d, J = 4.5 Hz, 1H), 8.29 (s, 2H), 9.57 (s, 1H), 9.89 (s,1H), 10.82 (s, 1H); 19F NMR ( 1094 5-Fluoro-N2-(3-fluoro-4-methoxyphenyl)-N4-[3- (N-2- 1H NMR (DMSO-d6): d 3.63 (s,4H), 3.79 (s, 3H), 6.96 (d, J = 9.3 Hz, + −imidazolin-2-yl)aminophenyl]-2,4-pyrimidinediamine 1H), 7.04 (t, J = 9.3Hz, 1H), 7.28 (m, 1H), 7.36 (t, J = 8.1 Hz, 1H), 7.63 (dd, J = 2.1, 13.8Hz, 1H), 7.68 (d, J = 9.6 Hz, 1H), 7.80 (s, 1H), 8.18 (d, J = 4.2 Hz,1H), 8.27 (s, 1H), 9.56 (s, 1095 N2-(3,5-Dimethylphenyl)-5-fluoro-N4-[3- (N-2-imidazolin-2- 1H NMR(DMSO-d6): d 2.20 (s, 6H), 3.60 (s, 4H), 6.92 (s, 1H), 6.98 + −yl)aminophenyl]-2,4-pyrimidinediamine (m, 1H), 7.22 (s, 1H), 7.35 (t, J= 8.1 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.80 (s, 1H), 8.21 (d, J = 4.2Hz, 1H), 8.26 (s, 2H), 9.60 (s, 1H), 9.86 (s, 1H), 10.80 (s, 1H); 19FNMR (282 MHz, D 1096 N2- (3,5-Dimethoxyphenyl)-5-fluoro-N4-[3-(N-2-imidazolin-2- 1H NMR (DMSO-d6): d 3.62 (s, 4H), 3.66 (s, 6H), 6.13(t, J = 2.1 Hz, + − − yl)aminophenyl]-2,4-pyrimidinediamine 1H), 6.92(d, J = 2.1 Hz, 1H), 6.95 (dd, J = 1.5, 8.4 Hz, 1H), 7.34 (t, J = 8.4Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.93 (s, 1H), 8.20 (d, J = 3.9 Hz,1H), 8.26 (s, 2H), 9.61 (s, 1H), 9.81 (s, 1097 5-Fluoro-N4-[3-(N-2-imidazolin-2-yl)aminophenyl]-N2- (3- 1H NMR (DMSO-d6): d 3.01 (t, J= 4.5 Hz, 4H), 3.60 (s, 4H), 3.70 (t, J = − −morpholinophenyl)-2,4-pyrimidinediamine 4.5 Hz, 4H), 6.51 (dd, J = 2.1,8.4 Hz, 1H), 6.90 (dd, J = 1.5, 7.8 Hz, 1H), 7.05 (t, J = 8.1 Hz, 1H),7.29 (m, 3H), 7.64 (d, J = 7.8 Hz, 1H), 8.01 (s, 1H), 8.12 (d, J = 3.6Hz, 1H), 9.20 ( 1098 N2-[3-(4-Ethoxycarbonylpiperazino)phenyl]-5-fluoro-N4-[3- (N- 1H NMR(DMSO-d6): d 1.20 (t, J = 7.2 Hz, 3H), 3.02 (t, J = 5.4 Hz, 4H), − −2-imidazolin-2-yl)aminophenyl]-2,4-pyrimidinediamine 3.47 (t, J = 5.4Hz, 4H), 3.60 (s, 4H), 4.05 (q, J = 7.2 Hz, 2H), 6.53 (dd, J = 1.5, 8.4Hz, 1H), 6.90 (d, J = 8.1 Hz, 1H), 7.06 (t, J = 8.1 Hz, 1H), 7.30 (m,3H), 7.66 (d, J = 8.7 Hz, 1H), 7 1099 5-Fluoro-N4-[3-(N-2-imidazolin-2-yl)aminophenyl]-N2-[4- (4- 1H NMR (DMSO-d6): d 3.30(m, 4H), 3.62 (s, 4H), 6.84 (d, J = 9.0 Hz, − −methylpiperazino)phenyl]-2,4-pyrimidinediamine 2H), 6.91 (d, J = 8.1 Hz,1H), 7.35 (t, J = 8.1 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.73 (d, J =8.4 Hz, 1H), 7.80 (s, 1H), 8.09 (d, J = 3.3 Hz, 1H), 8.27 (s, 1H), 9.06(s, 1H), 9.44 (s, 1H); 1 1100 5-Fluoro-N4-[3-(N-2-imidazolin-2-yl)aminophenyl]-N2-[4- (4- 1H NMR (DMSO-d6): d 3.00(t, J = 5.1 Hz, 4H), 3.50 (t, J = 4.5 Hz, 4H), − −methoxycarbonylpiperazino)phenyl]-2,4-pyrimidinediamine 3.61 (s, 7H),6.84 (d, J = 9.0 Hz, 2H), 6.91 (dd, J = 1.5, 7.5 Hz, 1H), 7.34 (t, J =7.8 Hz, 1H), 7.52 (d, J = 8.7 Hz, 2H), 7.66 (d, J = 8.1 Hz, 1H), 7.94(s, 1H), 8.08 (d, J = 3.6 Hz, 1H), 9 1101 N4-(5-tert-Butyl-1H-pyrazol-3-yl)-N2-[3- (4- 1H NMR (CDCl3): d 1.28 (t, J =7.2 Hz, 3H), 1.31 (s, 9H), 3.13 (t, J = + −ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4- 5.1 Hz, 4H), 3.60 (t, J =5.4 Hz, 4H), 4.15 (q, J = 7.2 Hz, 2H), 6.35 (s, pyrimidinediamine 1H),6.61 (m, 1H), 7.03 (s, 1H), 7.18 (m, 2H), 7.73 (br, 1H), 7.90 (d, J =3.3 Hz, 1H), 8.20 (br, 1H); 19F NMR (282 1102 N2-[4-(4-Acetylpiperazino)phenyl]-N4- (5-tert-butyl-1H-pyrazol- LCMS: ret.time: 8.02 min.; purity: 94.49%; MS (m/e): 453.29 (MH+). + + −3-yl)-5-fluoro-2,4-pyrimidinediamine 1103 N4-(5-tert-Butyl-1H-pyrazol-3-yl)-5-fluoro-N2-[4- (4- LCMS: ret. time:10.38 min.; purity: 97.48%; MS (m/e): 469.35 (MH+). + + −methoxycarbonylpiperazino)phenyl]-2,4-pyrimidinediamine 1104 N4-(5-tert-Butyl-1 H-pyrazol-3-yl)-5-fluoro-N2-[4- (4- 1H NMR (DMSO-d6): d1.26 (s, 9H), 2.61 (m, 7H), 3.00 (m, 4H), 6.30 + + −methylpiperazino)phenyl]-2,4-pyrimidinediamine (br, 1H), 6.86 (d, J =8.4 Hz, 2H), 7.48 (d, J = 9.3 Hz, 2H), 7.97 (s, 1H); 19F NMR (282 MHz,DMSO-d6): d - 165.34; LCMS: ret. time: 6.04 min.; purity: 90.75%; MS(m/e): 425 (MH+). 1105 N2-[4-(4-Acetylpiperazino)phenyl]-5-fluoro-N4-[3- (N-2- 1H NMR (DMSO-d6): d2.04 (s, 3H), 2.97 (t, J = 4.8 Hz, 2H), 3.04 (t, J = − −imidazolin-2-yl)aminophenyl]-2,4-pyrimidinediamine 4.8 Hz, 2H), 3.57 (m,4H), 3.61 (s, 4H), 6.84 (d, J = 9.0 Hz, 2H), 6.90 (d, J = 9.3 Hz, 1H),7.33 (t, J = 7.8 Hz, 1H), 7.50 (d, J = 8.7 Hz, 2H), 7.69 (d, J = 8.7 Hz,1H), 7.79 (s, 1H), 8.08 1106 N2-[3-(4-Acetylpiperazino)phenyl]-5-fluoro-N4-[3- (N-2- LCMS: ret. time: 7.31min.; purity: 84.11%; MS (m/e): 490.34 (MH+). − −imidazolin-2-yl)aminophenyl]-2,4-pyrimidinediamine 1107N4-Cyclobutyl-N2-[2- (ethoxycarbonyl)indol-7-yl]-5-fluoro-2,4- 1H NMR(CDCl3): d 1.42 (t, J = 7.2 Hz, 3H), 1.63-2.06 (m, 4H), 2.27- + +pyrimidinediamine 2.36 (m, 2H), 4.41 (q, J = 7.2 Hz, 2H), 5.17 (d, J =6.0 Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H), 7.14 (d, 1H), 7.22 (m, 2H), 7.28(br, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.76 (d, J = 3.6 Hz, 1H), 10.68 1108N4-Cyclobutyl-5-fluoro-N2- (3-morpholinophenyl)-2,4- 1H NMR (CDCl3): d1.73-2.05 (m, 4H), 2.40-2.50 (m, 2H), 3.20 (t, J = + + −pyrimidinediamine 4.8 Hz, 4H), 3.88 (t, J = 4.8 Hz, 4H), 4.60 (m, J =7.8 Hz, 1H), 5.14 (d, J = 6.3 Hz, 1H), 6.57 (dd, J = 2.4, 8.1 Hz, 1H),6.97 (dd, J = 1.8, 7.5 Hz, 1H), 7.06 (br, NH, 1H), 7.19 (t, J = 8.1 Hz1109 N4-Cyclobutyl-N2-[3- (4-ethoxycarbonylpiperazino)pheny]-5- 1H NMR(CDCl3): d 1.29 (t, J = 6.9 Hz, 3H), 1.71-2.02 (m, 4H), 2.41- + −fluoro-2,4-pyrimidinediamine 2.51 (m, 2H), 3.18 (t, J = 5.1 Hz, 4H),3.64 (t, J = 5.1 Hz, 4H), 4.17 (q, J = 6.9 Hz, 2H), 4.59 (m, J = 8.1 Hz,1H), 5.16 (d, J = 7.8 Hz, 1H), 6.58 (dd, J = 2.4, 8.1 Hz, 1H), 6.97 (dd,J = 1.8, 1110 N4-Cyclobutyl-5-fluoro-N2-[4-(4-methylpiperazino)phenyl]-2,4- 1H NMR (CDCl3): d 1.65-1.74 (m, 2H),1.85-1.95 (m, 2H), 2.19-2.33 + − pyrimidinediamine (m, 2H), 2.71 (s,3H), 3.15 (t, 4H), 3.32 (t, J = 4.8 Hz, 4H), 4.36 (m, J = 8.1 Hz, 1H),6.80 (d, J = 9.0 Hz, 2H), 7.36 (d, J = 9.3 Hz, 2H), 7.55 (d, J = 4.2 Hz,1H); 19F NMR (282 MHz, CDCl3): d 1111 N4-Cyclobutyl-N2-[4-(4-ethoxycarbonylpiperazino)phenyl]-5- 1H NMR (CDCl3): d 1.31 (t, 3H),1.50-2.04 (m, 4H), 2.41-2.50 (m, 2H), + − fluoro-2,4-pyrimidinediamine3.08 (t, J = 4.8 Hz, 4H), 3.64 (t, J = 5.1 Hz, 4H), 4.17 (q, 2H), 4.52(m, J = 7.8 Hz, 1H), 5.18 (d, J = 6.6 Hz, 1H), 6.90 (d, J = 9.0 Hz, 2H),7.07 (br, 1H), 7.45 (d, J = 9.0 Hz, 2H), 7.70 ( 1112 N2-[3-(4-Acetylpiperazino)phenyl]-N4- (3-cyclopropyl-1H- LCMS: ret. time: 9.04min.; purity: 87.21%; MS (m/e): 437.32 (MH+). + + +pyrazol-5-yl)-5-fluoro-2,4-pyrimidinediamine 1113 N4-(3-Cyclopropyl-1H-pyrazol-5-yl)-5-fluoro-N2-[4- (4- 1H NMR (CDCl3): d0.54-0.64 (m, 2H), 0.76-0.86 (m, 2H), 1.74 (m, + + −methylpiperazino)phenyl]-2,4-pyrimidinediamine 1H), 2.42 (s, 3H), 2.76(br, 4H), 3.17 (t, J = 4.8 Hz, 4H), 5.90 (br, 1H), 6.82 (d, J = 8.7 Hz,2H), 7.29 (d, J = 8.7 Hz, 2H), 7.71 (d, J = 3.6 Hz, 1H); 19F NMR (282MHz, CDCl3): d - 167.69; LCM 1114 N4-(3-Cyclopropyl-1H-pyrazol-5-yl)-5-fluoro-N2- (3- LCMS: ret. time: 8.57min.; purity: 88.76%; MS (m/e): 396.24 (MH+). + + −morpholinophenyl)-2,4-pyrimidinediamine 1115 N4-(3-Cyclopropyl-1H-pyrazol-5-yl)-N2-[3- (4- 1H NMR (DMSO-d6): d 0.67 (m,2H), 0.88 (m, 2H), 1.19 (t, J = 7.1 Hz, + +ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4- 3H), 1.85 (m, 1H), 3.06(m, 4H), 3.48 (m, 4H), 4.05 (q, J = 7.1 Hz, 2H), pyrimidinediamine 6.52(d, J = 8.1 Hz, 1H), 7.07 (m, 1H), 7.20 (m, 2H); LCMS: ret. time: 11.80min.; purity: 79.43%; MS (m/e): 467.30 1116 N4-(3-Cyclopropyl-1H-pyrazol-5-yl)-N2-[4- (4- 1H NMR (DMSO-d6): d 0.62 (m,2H), 0.90 (m, 2H), 1.20 (t, J = 7.2 Hz, + +ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4- 3H), 1.84 (m, J = 3.9 Hz,1H), 3.08 (br, 4H), 3.44 (br, 4H), 4.05 (q, J = pyrimidinediamine 6.9Hz, 2H), 6.12 (br, 1H), 6.93 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.4 Hz,2H), 8.02 (d, J = 4.2 Hz, 1H), 9.37 (br, 1H 1117 2-Chloro-5-fluoro-N4-(3,4-dihydro-2H,4H-5-pyrid[1,4]oxazin-6- 1H NMR (DMSO-d6): d 3.40 (t, J= 4.5 Hz, 2H), 4.10 (t, J = 4.5 Hz, 2H), − − yl)-4-pyrimidineamine 6.92(d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.1 Hz, 1H), 8.27 (d, J = 3.6 Hz, 1H),9.80 (br, 1H); 19F NMR (282 MHz, DMSO-d6): d - 152.34; LCMS: ret. time:9.69 min.; purity: 93.93%; MS (m/e): 2 1118 N4-(1-tert-Butoxycarbonylazetidin-3-yl)-5-fluoro-N2- (4- 1H NMR (CDCl3): d1.45 (s, 9H), 3.18 (t, J = 4.8 Hz, 4H), 3.89 (m, 4H), + +morpholinophenyl)-2,4-pyrimidinediamine 3.96 (m, 2H), 4.28 (m, 2H), 4.69(m, 1H), 6.93 (d, J = 9.0 Hz, 2H), 7.36 (d, J = 9.3 Hz, 2H), 7.66 (d, J= 3.6 Hz, 1H); 19F NMR (282 MHz, CDCl3): d - 163.92; LCMS: ret. time:9.28 min.; p 1119 N2-[4- (4-Acetylpiperazino)phenyl]-N4- (1-tert- 1H NMR(CDCl3): d 1.46 (s, 9H), 2.16 (s, 3H), 3.15 (p, J = 5.1 Hz, 4H), + −butoxycarbonylazetidin-3-yl)-5-fluoro-2,4-pyrimidinediamine 3.64 (t, J =5.1 Hz, 2H), 3.78 (t, J = 5.1 Hz, 2H), 3.91 (dd, J = 5.4, 9.9 Hz, 2H),4.30 (dd, J = 7.8, 9.6 Hz, 2H), 4.70 (m, 1H), 6.91 (d, J = 9.3 Hz, 2H),7.38 (d, J = 9.3 Hz, 2H), 7.72 (d, 1120 N2-[3-(4-Acetylpiperazino)phenyl]-N4- (1-tert- 1H NMR (CDCl3): d 1.45 (s, 9H),2.16 (s, 3H), 3.21 (m, 4H), 3.64 (m, − −butoxycarbonylazetidin-3-yl)-5-fluoro-2,4-pyrimidinediamine 2H), 3.78(m, 2H), 3.99 (dd, J = 4.8, 9.0 Hz, 2H), 4.30 (dd, J = 7.8, 9.3 Hz, 2H),4.74 (m, 1H), 6.75 (d, J = 5.1 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 7.19(m, 1H), 7.26 (m, 1H), 7.69 (d, J = 4 1121 N4- (3-Cyclopropyl-1H-pyrazol-5-yl)-5-fluoro-N2- (4- LCMS: ret. time: 7.80 min.; purity:96.17%; MS (m/e): 396.22 (MH+). + + −morpholinophenyl)-2,4-pyrimidinediamine 1122 N4-(1-tert-Butoxycarbonylazetidin-3-yl)-N2-[4- (4- LCMS: ret. time: 10.44min.; purity: 82.19%; MS (m/e): 516.26 (MH+). + −ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4- pyrimidinediamine 1123N4- (Azetidin-3-yl)-5-fluoro-N2- (4-morpholinophenyl)-2,4- LCMS: ret.time: 2.12 min.; purity: 88.18%; MS (m/e): 345.21 (MH+). − +pyrimidinediamine 1124 N2-[4- (4-Acetylpiperazino)phenyl]-N4-(azetidin-3-yl)-5-fluoro- LCMS: ret. time: 2.33 min.; purity: 92.29%; MS(m/e): 386.25 (MH+). − − 2,4-pyrimidinediamine 1125 N4-(Azetidin-3-yl)-N2-[4- (4-ethoxycarbonylpiperazino)phenyl]- LCMS: ret.time: 7.44 min.; purity: 85.69%; MS (m/e): 416 (MH+). − −5-fluoro-2,4-pyrimidinediamine 1126 N4- (Azetidin-3-yl)-5-fluoro-N2-(3-morpholinophenyl)-2,4- LCMS: ret. time: 2.85 min.; purity: 100%; MS(m/e): 345.24 (MH+). − + pyrimidinediamine 1127 N2-[3-(4-Acetylpiperazino)phenyl]-N4- (azetidin-3-yl)-5-fluoro- LCMS: ret.time: 3.10 min.; purity: 88.30%; MS (m/e): 386.28 (MH+). + −2,4-pyrimidinediamine 1128 N4-(3,4-Dihydro-2H,4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2- (4- 1H NMR(DMSO-d6): d 3.00 (t, J = 4.8 Hz, 4H), 3.38 (t, 2H), 3.72 (t, J = + −morpholinophenyl)-2,4-pyrimidinediamine 4.8 Hz, 4H), 4.08 (t, J = 4.2Hz, 2H), 6.50 (br, 1H), 6.82 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 8.1 Hz,1H), 7.20 (d, J = 8.1 Hz, 1H), 7.48 (d, J = 9.3 Hz, 2H), 7.99 (d, J =3.6 Hz, 1H), 8.65 ( 1129 N4- (1-tert-Butoxycarbonylazetidin-3-yl)-N2-[3-(4- LCMS: ret. time: 11.35 min.; purity: 86.05%; MS (m/e): 516.32 (MH+).− ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4- pyrimidinediamine 1130N4- (Azetidin-3-yl)-N2-[3- (4-ethoxycarbonylpiperazino)phenyl]- LCMS:ret. time: 8.39 min.; purity: 96.94%; MS (m/e): 416 (MH+). −5-fluoro-2,4-pyrimidinediamine 1131 N4- (Azetidin-3-yl)-5-fluoro-N2-[4-(4-methylpiperazino)phenyl]- LCMS: ret. time: 1.20 min.; purity: 96.44%;MS (m/e): 358.24 (MH+). − 2,4-pyrimidinediamine 1132 N4-(3,4-Dihydro-2H,4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-[3- 1H NMR(DMSO-d6): d 3.38 (t, 2H), 4.08 (t, J = 4.5 Hz, 2H), 6.52 (br, +(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 1H), 6.78 (d, J = 8.1 Hz,1H), 7.27 (m, 3H), 7.50 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 8.01 (s, 1H),8.08 (d, J = 3.6 Hz, 1H), 8.38 (s, 1H), 8.82 (s, 1H), 9.35 (s, 1H); 19FNMR (282 MHz, DMSO 11332-Chloro-N4-cyclobutyl-5-fluoro-N4-methyl-4-pyrimidineamine 1H NMR(CDCl3): d 1.68-1.76 (m, 2H), 2.17-2.25 (m, 4H), 3.14 (d, J = − 3.0 Hz,3H), 4.79 (m, J = 8.4 Hz, 1H), 7.85 (d, J = 6.0 Hz, 1H); 19F NMR (282MHz, CDCl3): d - 150.50; LCMS: ret. time: 13.83 min.; purity: 96.47%; MS(m/e): 216.10 (MH+). 1134 N2-[4- (4-Acetylpiperazino)phenyl]-N4-(3,4-dihydro-2H,4H-5- 1H NMR (DMSO-d6): d 2.03 (s, 3H), 2.97 (t, J = 5.1Hz, 2H), 3.03 (t, J = + +pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 5.1 Hz, 2H), 3.39(t, 2H), 3.56 (t, 4H), 4.08 (t, J = 4.2 Hz, 2H), 6.51 (s, 1H), 6.84 (d,J = 9.0 Hz, 2H), 6.93 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H),7.49 (d, J = 9.0 Hz, 2H), 7.99 1135 N4-(3,4-Dihydro-2H,4H-5-pyrid[1,4]oxazin-6-yl)-N2-[4- (4- 1H NMR (DMSO-d6):d 1.19 (t, J = 7.2 Hz, 3H), 2.99 (t, J = 5.4 Hz, 4H), + +ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4- 3.39 (t, 2H), 3.49 (t,4H), 4.04 (q, J = 7.2 Hz, 2H), 4.08 (t, J = 4.8 Hz, pyrimidinediamine2H), 6.51 (s, 1H), 6.84 (d, J = 9.3 Hz, 2H), 6.93 (d, J = 8.4 Hz, 1H),7.19 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 9.0 Hz 1136 N4-(3,4-Dihydro-2H,4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2- (3- 1H NMR(DMSO-d6): d 2.99 (t, J = 5.1 Hz, 4H), 3.39 (t, 2H), 3.69 (t, J = + +morpholinophenyl)-2,4-pyrimidinediamine 4.8 Hz, 4H), 4.08 (t, J = 4.2Hz, 2H), 6.50 (m, 2H), 6.91 (d, J = 8.4 Hz, 1H), 7.04 (t, J = 8.1 Hz,1H), 7.19 (m, 3H), 8.04 (d, J = 3.6 Hz, 1H), 8.74 (s, 1H), 9.02 (s, 1H);19F NMR (282 MH 1137 N2-[3- (4-Acetylpiperazino)phenyl]-N4-(3,4-dihydro-2H,4H-5- 1H NMR (DMSO-d6): d 2.03 (s, 3H), 2.98 (t, J = 4.8Hz, 2H), 3.05 (t, J = + +pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 4.8 Hz, 2H), 3.39(t, 2H), 3.53 (t, J = 5.4 Hz, 4H), 4.08 (t, 2H), 6.50 (m, 2H), 6.91 (d,J = 8.4 Hz, 1H), 7.04 (t, J = 8.4 Hz, 1H), 7.21 (m, 3H), 8.04 (d, J =3.6 Hz, 1H), 8.75 (s, 1H), 9 1138 N4-(3,4-Dihydro-2H,4H-5-pyrid[1,4]oxazin-6-yl)-N2-[3- (4- 1H NMR (DMSO-d6):d 1.20 (t, J = 7.2 Hz, 3H), 3.01 (t, J = 4.8 Hz, 4H), + +ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4- 3.41 (t, 2H), 3.46 (t, J= 4.8 Hz, 4H), 4.08 (t, 2H), 6.50 (m, 2H), 6.91 (d, pyrimidinediamine J= 8.4 Hz, 1H), 7.04 (t, J = 8.4 Hz, 1H), 7.19 (d, J = 8.1 Hz, 2H), 7.25(t, 1H), 8.04 (d, J = 3.6 Hz, 1H), 8.73 1139N4-Cyclobutyl-5-fluoro-N4-methyl-N2- (4-morpholinophenyl)- 1H NMR(DMSO-d6): d 1.56-1.69 (m, 2H), 2.07-2.27 (m, 4H), 3.07 (t, + −2,4-pyrimidinediamine J = 4.5 Hz, 4H), 3.12 (d, J = 3.0 Hz, 3H), 3.73(t, J = 4.5 Hz, 4H), 4.76 (m, J = 8.4 Hz, 1H), 6.92 (d, J = 9.0 Hz, 2H),7.42 (d, J = 8.7 Hz, 2H), 7.97 (d, J = 7.2 Hz, 1H), 9.36 (br, 1H); 19FNMR 1140 N2-[4- (4-Acetylpiperazino)phenyl]-N4-cyclobutyl-5-fluoro-N4-1H NMR (DMSO-d6): d 1.59-1.69 (m, 2H), 2.03 (s, 3H), 2.10-2.27 (m, + −methyl-2,4-pyrimidinediamine 4H), 3.03 (t, J = 4.5 Hz, 2H), 3.11 (d, J =3.0 Hz, 5H), 3.56 (t, 4H), 4.76 (m, J = 7.5 Hz, 1H), 6.93 (d, J = 9.0Hz, 2H), 7.45 (d, J = 9.0 Hz, 2H), 7.96 (d, J = 7.2 Hz, 1H), 9.26 (br,1H); LCMS 1141 N4-(3,4-Dihydro-2H,4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-[4- 1H NMR(DMSO-d6): d 2.23 (s, 3H), 3.03 (t, 4H), 3.29 (m 4H), 3.38 (t, + + −(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine 2H), 4.08 (t, J = 4.5Hz, 2H), 6.50 (br, 1H), 6.81 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.4 Hz,1H), 7.20 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 9.0 Hz, 2H), 7.98 (d, J =3.6 Hz, 1H), 8.64 (br, 1H), 1142 N4-(3,4-Dihydro-2H,4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-[3- 1H NMR(DMSO-d6): d 2.20 (s, 3H), 2.41 (t, 4H), 3.03 (t, 4H), 3.38 (t, + + −(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine 2H), 4.08 (t, J = 4.8Hz, 2H), 6.50 (m, 2H), 6.91 (d, J = 7.8 Hz, 1H), 7.02 (t, J = 7.8 Hz,1H), 7.20 (m, 3H), 8.03 (d, J = 3.6 Hz, 1H), 8.72 (s, 1H), 8.99 (s, 1H);19F NMR (282 MHz, DMSO- 1143 N4-(3,4-Dihydro-2H,4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-[3- 1H NMR(DMSO-d6): d 3.53 (t, J = 4.2 Hz, 2H), 4.16 (t, J = 4.2 Hz, 2H), + + −(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 6.84 (d, J = 8.7 Hz, 1H),7.24 (d, J = 8.7 Hz, 1H), 7.35 (s, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.56(dt, J = 1.2, 8.1 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 8.18 (s, 1H), 8.32(d, J = 3.3 Hz, 1H), 8 1144 N4-(3-Cyclopropyl-1H-pyrazol-5-yl)-5-fluoro-N2-[3- (oxazol-2- 1H NMR(DMSO-d6): d 0.61-0.66 (m, 2H), 0.86 (m, 2H), 1.81 (m, 1H), + + − +yl)phenyl]-2,4-pyrimidinediamine 6.41 (br, 1H), 7.35 (m, 2H), 7.52 (d, J= 7.5 Hz, 1H), 7.86 (s, 1H), 8.04 (s, 1H), 8.19 (m, 2H), 9.34 (s, 1H),9.60 (s, 1H); 19F NMR (282 MHz, DMSO-d6): d - 163.42; LCMS: ret. time:9.50 mi 1145 N4-(3,4-Dihydro-2H,4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 3.49 (t, 2H), 3.61 (s, 3H), 3.69 (s, 6H), 4.14 (t, + + − +(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine J = 4.5 Hz, 2H), 6.94 (d,J = 7.8 Hz, 1H), 7.07 (s, 2H), 7.14 (d, 1H), 8.20 (d, J = 3.6 Hz, 1H),9.75 (s, 1H); LCMS: ret. time: 8.80 min.; purity: 100%; MS (m/e): 429.45(MH+). 1146 N2- (3-Chloro-4-methoxyphenyl)-N4- (3,4-dihydro-2H,4H-5- 1HNMR (DMSO-d6): d 3.39 (s, 2H), 3.78 (s, 3H), 4.08 (t, J = 3.9 Hz, + −pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 2H), 6.54 (br,1H), 6.95 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 7.13 (d, J =8.4 Hz, 1H), 7.46 (dd, J = 2.4, 9.0 Hz, 1H), 7.84 (d, J = 2.4 Hz, 1H),8.04 (d, J = 3.3 Hz, 1H), 8.80 (s, 1H 1147N4-Cyclobutyl-5-fluoro-N4-methyl-N2-[4- (4- 1H NMR (DMSO-d6): d1.56-1.68 (m, 2H), 2.10-2.26 (m, 4H), 2.21 (s, + + − +methylpiperazino)phenyl]-2,4-pyrimidinediamine 3H), 2.44 (t, 4H), 3.02(t, J = 4.8 Hz, 4H), 3.05 (d, J = 2.7 Hz, 3H), 4.74 (m, J = 7.8 Hz, 1H),6.82 (d, J = 9.0 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 7.88 (d, J = 6.6 Hz,1H), 8.79 (br, 1H); 19F 1148 N4-Cyclobutyl-N2-[4-(4-ethoxycarbonylpiperazino)phenyl]-5- 1H NMR (DMSO-d6): d 1.19 (t, J =7.2 Hz, 3H), 1.56-1.69 (m, 2H), + + −fluoro-N4-methyl-2,4-pyrimidinediamine 2.07-2.27 (m, 4H), 3.06 (t, J =4.8 Hz, 4H), 3.11 (d, J = 3.0 Hz, 3H), 3.50 (t, 4H), 4.05 (q, J = 7.2Hz, 2H), 4.76 (m, J = 8.4 Hz, 1H), 6.93 (d, J = 9.0 Hz, 2H), 7.43 (d, J= 8.7 Hz, 2H), 7.97 (d, 1149 N4-Cyclobutyl-5-fluoro-N4-methyl-N2-(3-morpholinophenyl)- 1H NMR (DMSO-d6): d 1.57-1.70 (m, 2H), 2.13-2.24(m, 4H), 3.07 (t, + − 2,4-pyrimidinediamine J = 4.8 Hz, 4H), 3.11 (d, J= 3.3 Hz, 3H), 3.73 (t, J = 4.5 Hz, 4H), 4.78 (m, J = 8.7 Hz, 1H), 6.57(m, 1H), 7.08 (m, 2H), 7.24 (m, 1H), 7.98 (d, J = 6.9 Hz, 1H), 9.19 (br,1H); LCMS: ret. time 1150 N2-[3-(4-Acetylpiperazino)phenyl]-N4-cyclobutyl-5-fluoro-N4- 1H NMR (CDCl3): d1.66-1.78 (m, 2H), 2.15 (s, 3H), 2.22 (m, 4H), + −methyl-2,4-pyrimidinediamine 3.17 (d, J = 2.7 Hz, 3H), 3.22 (m, 4H),3.62 (t, J = 4.8 Hz, 2H), 3.77 (t, J = 5.1 Hz, 2H), 4.85 (m, J = 8.4 Hz,1H), 6.58 (dd, J = 2.4, 8.1 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 7.19 (t,J = 8.1 Hz, 1151 N4-Cyclobutyl-5-fluoro-N4-methyl-N2-[3- (4- 1H NMR(CDCl3): d 1.63-1.77 (m, 2H), 2.21 (m, 4H), 2.45 (s, 3H), + + −methylpiperazino)phenyl]-2,4-pyrimidinediamine 2.72 (t, J = 4.8 Hz, 4H),3.13 (d, J = 3.9 Hz, 3H), 3.32 (t, J = 4.8 Hz, 4H), 4.84 (m, J = 8.7 Hz,1H), 6.56 (dd, J = 2.4, 8.1 Hz, 1H), 6.82 (br, 1H), 7.00 (d, J = 8.1 Hz,1H), 7.17 (t, J = 7.8 Hz, 1152 N4-Cyclobutyl-N2-[3-(4-ethoxycarbonylpiperazino)phenyl]-5- 1H NMR (DMSO-d6): d 1.19 (t, J =7.2 Hz, 3H), 1.60-1.70 (m, 2H), + −fluoro-N4-methyl-2,4-pyrimidinediamine 2.13-2.28 (m, 4H), 3.08 (t, J =5.1 Hz, 4H), 3.12 (d, J = 3.3 Hz, 3H), 3.50 (t, 4H), 4.05 (q, J = 7.2Hz, 2H), 4.79 (m, J = 9.0 Hz, 1H), 6.59 (d, J = 6.9 Hz, 1H), 7.09 (m,2H), 7.27 (s, 1H), 7.99 1153 N2-(2-Aminocarbonyl-5-benzoxy-4-methoxyphenyl)-N4- 1H NMR (DMSO-d6): d1.69-1.78 (m, 2H), 2.28 (m, 4H), 3.36 (d, J = − −cyclobutyl-5-fluoro-N4-methyl-2,4-pyrimidinediamine 3.3 Hz, 3H), 3.90(s, 3H), 4.94 (m, 1H), 5.30 (s, 2H), 7.12 (s, 1H), 7.35-7.48 (m, 6H),9.04 (d, J = 9.0 Hz, 1H); LCMS: ret. time: 11.25 min.; purity: 98.01%;MS (m/e): 435.22 (M-16). 1154 N2-(4-Benzamidophenyl)-N4-cyclobutyl-5-fluoro-2,4- 1H NMR (DMSO-d6): d1.62-1.74 (m, 2H), 2.02-2.15 (m, 2H), 2.23- + − pyrimidinediamine 2.31(m, 2H), 4.50 (m, J = 8.1 Hz, 1H), 7.46-7.68 (m, 8H), 7.84 (d, J = 3.6Hz, 1H), 7.92 (td, J = 1.2, 6.6 Hz, 2H), 8.99 (s, 1H), 10.07 (s, 1H);19F NMR (282 MHz, DMSO-d6): d - 167.01; LCMS: ret 1155N4-Cyclopentyl-5-fluoro-N2- (4-morpholinophenyl)-2,4- 1H NMR (DMSO-d6):d 1.54 (m, 4H), 1.70 (m, 2H), 1.94 (m, 2H), 2.98 + − pyrimidinediamine(t, J = 4.8 Hz, 4H), 3.70 (t, J = 4.8 Hz, 4H), 4.30 (q, J = 6.9 Hz, 1H),6.80 (d, J = 9.0 Hz, 2H), 7.22 (d, J = 6.9 Hz, 1H), 7.55 (d, J = 9.3 Hz,2H), 7.76 (d, J = 3.6 Hz, 1H), 8.74 (br, 1H); 19F 1156 N2-[4-(4-Acetylpiperazino)phenyl]-N4-cyclopentyl-5-fluoro-2,4- 1H NMR(DMSO-d6): d 1.54 (m, 4H), 1.70 (m, 2H), 1.93 (m, 2H), 2.02 + −pyrimidinediamine (s, 3H), 2.94 (t, J = 4.8 Hz, 2H), 3.01 (t, J = 5.1Hz, 2H), 3.54 (t, 4H), 4.30 (q, J = 6.9 Hz, 1H), 6.83 (d, J = 8.7 Hz,2H), 7.24 (d, J = 7.2 Hz, 1H), 7.56 (d, J = 9.0 Hz, 2H), 7.76 (d, J =3.9 1157 N4-Cyclopentyl-5-fluoro-N2-[4- (4-methylpiperazino)phenyl]- 1HNMR (DMSO-d6): d 1.54 (m, 4H), 1.70 (m, 2H), 1.93 (m, 2H), 2.21 + −2,4-pyrimidinediamine (s, 3H), 2.44 (t, 4H), 3.01 (t, 4H), 4.30 (q, J =6.3 Hz, 1H), 6.79 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 6.3 Hz, 1H), 7.53(d, J = 9.0 Hz, 2H), 7.76 (d, J = 3.0 Hz, 1H), 8.72 (br, 1H); 19F NMR(28 1158 N4-Cyclopentyl-5-fluoro-N2- (3-morpholinophenyl)-2,4- 1H NMR(DMSO-d6): d 1.52 (m, 4H), 1.71 (m, 2H), 1.93 (m, 2H), 3.03 + −pyrimidinediamine (t, J = 4.8 Hz, 4H), 3.72 (t, J = 4.8 Hz, 4H), 4.36(m, 1H), 6.45 (d, J = 9.6 Hz, 1H), 7.02 (t, J = 7.8 Hz, 1H), 7.13 (d, J= 8.1 Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.42 (s, 1H), 7.80 (d, J = 3.61159 N2-[3- (4-Acetylpiperazino)phenyl]-N4-cyclopentyl-5-fluoro-2,4- 1HNMR (DMSO-d6): d 1.53 (m, 4H), 1.71 (m, 2H), 1.94 (m, 2H), 2.03 + −pyrimidinediamine (s, 3H), 3.02 (t, J = 5.1 Hz, 2H), 3.08 (t, J = 4.8Hz, 2H), 3.55 (t, 4H), 4.36 (q, J = 6.6 Hz, 1H), 6.47 (d, J = 7.8 Hz,1H), 7.03 (t, J = 8.1 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 7.30 (d, J =7.2 1160 N4-Cyclopentyl-5-fluoro-N2-[3- (4-methylpiperazino)phenyl]-LCMS: ret. time: 6.49 min.; purity: 79.17%; MS (m/e): 371.23 (MH+). + −2,4-pyrimidinediamine 1161 N4-Cyclopentyl-N2-[3-(4-ethoxycarbonylpiperazino)phenyl]-5- LCMS: ret. time: 10.76 min.;purity: 77.07%; MS (m/e): 429.50 (MH+). + − fluoro-2,4-pyrimidinediamine1162 N4-Cyclohexyl-5-fluoro-N2- (4-morpholinophenyl)-2,4- 1H NMR(DMSO-d6): d 1.14 (m, 1H), 1.31 (m, 4H), 1.64 (d, 1H), 1.75 + −pyrimidinediamine (m, 2H), 1.90 (m, 2H), 2.98 (t, J = 4.8 Hz, 4H), 3.71(t, J = 4.8 Hz, 4H), 3.86 (m, 1H), 6.80 (d, J = 9.3 Hz, 2H), 7.14 (d, J= 8.4 Hz, 1H), 7.55 (d, J = 9.0 Hz, 2H), 7.76 (d, J = 3.9 Hz, 1H), 81163 N2-[4- (4-Acetylpiperazino)phenyl]-N4-cyclohexyl-5-fluoro-2,4- 1HNMR (DMSO-d6): d 1.31 (m, 5H), 1.64 (d, 1H), 1.75 (m, 2H), 1.90 + −pyrimidinediamine (m, 2H), 2.02 (s, 3H), 2.94 (t, J = 4.8 Hz, 2H), 3.01(t, J = 5.1 Hz, 2H), 3.55 (m, 4H), 3.86 (m, 1H), 6.82 (d, J = 9.0 Hz,2H), 7.12 (d, J = 7.5 Hz, 1H), 7.55 (d, J = 8.7 Hz, 2H), 7.76 (d, J =1164 N4-Cyclohexyl-5-fluoro-N2-[4- (4-methylpiperazino)phenyl]-2,4- 1HNMR (DMSO-d6): d 1.31 (m, 5H), 1.64 (d, 1H), 1.75 (m, 2H), 1.90 + − +pyrimidinediamine (m, 2H), 2.21 (s, 3H), 2.46 (t, J = 4.8 Hz, 4H), 3.01(t, J = 4.8 Hz, 4H), 3.85 (m, 1H), 6.79 (d, J = 9.0 Hz, 2H), 7.12 (d, J= 8.4 Hz, 1H), 7.52 (d, J = 9.0 Hz, 2H), 7.76 (d, J = 3.9 Hz, 1H), 81165 N4-Cyclohexyl-N2-[4- (4-ethoxycarbonylpiperazino)phenyl]-5- 1H NMR(DMSO-d6): d 1.19 (t, J = 7.2 Hz, 3H), 1.31 (m, 5H), 1.64 (d, + +fluoro-2,4-pyrimidinediamine 1H), 1.76 (m, 2H), 1.90 (m, 2H), 2.97 (t, J= 4.8 Hz, 4H), 3.48 (t, 4H), 3.86 (m, 1H), 4.04 (q, J = 7.2 Hz, 2H),6.82 (d, J = 9.0 Hz, 2H), 7.12 (d, J = 6.9 Hz, 1H), 7.55 (d, J = 9.3 Hz,2H), 7 1166 N4-Cyclohexyl-5-fluoro-N2- (3-morpholinophenyl)-2,4- 1H NMR(DMSO-d6): d 1.27 (m, 5H), 1.63 (d, 1H), 1.76 (m, 2H), 1.87 + −pyrimidinediamine (m, 2H), 3.04 (t, J = 4.8 Hz, 4H), 3.72 (t, J = 4.8Hz, 4H), 3.90 (m, 1H), 6.46 (dd, J = 2.1, 7.8 Hz, 1H), 7.03 (t, J = 8.4Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.24 (m, 2H), 7.80 (d, J = 3.9 Hz,1167 N2-[3- (4-Acetylpiperazino)phenyl]-N4-cyclohexyl-5-fluoro-2,4- 1HNMR (DMSO-d6): d 1.31 (m, 5H), 1.61 (m, 1H), 1.76 (m, 2H), 1.87 + −pyrimidinediamine (m, 2H), 2.03 (s, 3H), 3.04 (t, 2H), 3.09 (t, 2H),3.56 (t, 4H), 3.90 (m, 1H), 6.48 (d, J = 9.0 Hz, 1H), 7.04 (t, J = 8.4Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.25 (m, 2H), 7.80 (d, J = 3.6 Hz,1168 N4-Cyclohexyl-5-fluoro-N2-[3- (4-methylpiperazino)phenyl]-2,4- 1HNMR (DMSO-d6): d 1.14 (m, 1H), 1.31 (m, 4H), 1.63 (d, 1H), 1.76 + −pyrimidinediamine (m, 2H), 1.86 (m, 2H), 2.26 (s, 3H), 3.09 (t, 4H),3.32 (t, 4H), 3.88 (m, 1H), 6.45 (d, J = 6.9 Hz, 1H), 7.01 (t, J = 8.1Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 7.24 (m, 2H), 7.80 (d, J = 3.9 Hz,1169 N4-Cyclohexyl-N2-[3- (4-ethoxycarbonylpiperazino)phenyl]-5- 1H NMR(DMSO-d6): d 1.19 (t, J = 6.9 Hz, 3H), 1.31 (m, 5H), 1.62 (d, + −fluoro-2,4-pyrimidinediamine 1H), 1.76 (m, 2H), 1.87 (m, 2H), 3.05 (t, J= 4.8 Hz, 4H), 3.49 (t, 4H), 3.90 (m, 1H), 4.05 (q, J = 7.2 Hz, 2H),6.48 (d, J = 4.5 Hz, 1H), 7.03 (t, J = 8.1 Hz, 1H), 7.16 (d, J = 6.6 Hz,1H), 7 1170 N2- (4-Benzamidophenyl)-N4-cyclopentyl-5-fluoro-2,4- 1H NMR(DMSO-d6): d 1.57 (m, 4H), 1.72 (m, 2H), 1.96 (m, 2H), 4.32 + −pyrimidinediamine (q, J = 7.5 Hz, 1H), 7.29 (d, J = 6.3 Hz, 1H),7.46-7.69 (m, 7H), 7.81 (d, J = 3.9 Hz, 1H), 7.92 (d, J = 9.6 Hz, 2H),8.97 (s, 1H), 10.05 (s, 1H); 19F NMR (282 MHz, DMSO-d6): d - 166.85;LCMS: 1171 N2- (2-Aminocarbonyl-5-benzoxy-4-methoxyphenyl)-N4- 1H NMR(DMSO-d6): d 1.60 (m, 4H), 1.74 (m, 2H), 1.96 (m, 2H), 3.85 + −cyclopentyl-5-fluoro-2,4-pyrimidinediamine (s, 3H), 4.43 (q, J = 6.9 Hz,1H), 5.24 (s, 2H), 7.06 (s, 1H), 7.31-7.50 (m, 6H), 8.53 (d, J = 7.2 Hz,1H), 8.70 (d, J = 6.9 Hz, 1H); 19F NMR (282 MHz, DMSO-d6): d - 155.92;LCMS: ret. time: 1172 N2-[4-(N-Acetyl-N-methylamino)phenyl]-N4-cyclopentyl-5- 1H NMR (DMSO-d6): d1.55 (m, 4H), 1.71 (m, 2H), 1.94 (m, 2H), 3.09 + −fluoro-2,4-pyrimidinediamine (s, 3H), 3.31 (s, 3H), 4.32 (q, J = 7.2 Hz,1H), 7.13 (d, J = 9.0 Hz, 2H), 7.34 (d, J = 7.2 Hz, 1H), 7.77 (d, J =8.7 Hz, 2H), 7.83 (d, J = 3.9 Hz, 1H), 9.14 (s, 1H); 19F NMR (282 MHz,DMSO-d6) 1173 N4-Cyclopentyl-5-fluoro-N2-[3- (N-2-imidazolin-2- 1H NMR(DMSO-d6): d 1.55 (m, 4H), 1.71 (m, 2H), 1.93 (m, 2H), 3.62 − −yl)aminophenyl]-2,4-pyrimidinediamine (s, 4H), 4.31 (q, J = 6.6 Hz, 1H),6.71 (d, J = 7.8 Hz, 1H), 7.25 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 7.2 Hz,1H), 7.53 (d, J = 7.5 Hz, 1H), 7.84 (s, 2H), 8.22 (s, 1H), 9.23 (s, 1H),10.54 (br, 1 1174 N2- (4-Benzamidophenyl)-N4-cyclohexyl-5-fluoro-2,4- 1HNMR (DMSO-d6): d 1.33 (m, 5H), 1.65 (d, 1H), 1.78 (m, 2H), 1.92 − + − +pyrimidinediamine (m, 2H), 3.88 (m, 1H), 7.22 (d, J = 8.1 Hz, 1H),7.46-7.69 (m, 7H), 7.81 (d, J = 3.9 Hz, 1H), 7.92 (d, J = 6.6 Hz, 2H),8.99 (s, 1H), 10.05 (s, 1H); 19F NMR (282 MHz, DMSO-d6): d - 166.98; LC1175 N2- (2-Aminocarbonyl-5-benzoxy-4-methoxyphenyl)-N4- 1H NMR(DMSO-d6): d 1.36 (m, 5H), 1.65 (d, 1H), 1.79 (m, 2H), 1.88 + −cyclohexyl-5-fluoro-2,4-pyrimidinediamine (m, 2H), 3.85 (s, 3H), 4.05(m, 1H), 5.24 (s, 2H), 7.06 (s, 1H), 7.31- 7.50 (m, 6H), 8.44 (d, J =7.5 Hz, 1H), 8.70 (d, J = 6.9 Hz, 1H); 19F NMR (282 MHz, DMSO-d6): d -156.00; LCMS: ret. tim 1176 N2-[4-(N-Acetyl-N-methylamino)phenyl]-N4-cyclohexyl-5- 1H NMR (DMSO-d6): d1.32 (m, 5H), 1.64 (d, 1H), 1.74 (m, 2H), 1.90 + −fluoro-2,4-pyrimidinediamine (m, 2H), 3.09 (s, 3H), 3.32 (s, 3H), 3.88(m, 1H), 7.13 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 7.5 Hz, 1H), 7.75 (d, J= 8.7 Hz, 2H), 7.83 (d, J = 3.9 Hz, 1H), 9.15 (s, 1H); 19F NMR (282 MHz,DMSO- 1177 N4-Cyclohexyl-5-fluoro-N2-[3- (N-2-imidazolin-2- LCMS: ret.time: 6.42 min.; purity: 86.49%; MS (m/e): 370.47 (MH+). − −yl)aminophenyl]-2,4-pyrimidinediamine 1178 N2,N4-Bis[3-(oxazol-2-yl)phenyl]-5-fluoro-2,4- 1H NMR (DMSO-d6): d 7.22 (t, J = 7.8Hz, 1H), 7.31 (d, J = 9.3 Hz, − − pyrimidinediamine 2H), 7.40 (t, J =8.1 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.81(d, J = 7.8 Hz, 1H), 8.08 (d, J = 7.5 Hz, 1H), 8.11 (d, 2H), 8.18 (d, J= 3.6 Hz, 1H), 8.24 (t, J = 1.8 Hz, 1 1179N4-Cyclobutyl-5-fluoro-N4-methyl-N2-[3- (oxazol-2-yl)phenyl]- 1H NMR(DMSO-d6): d 1.53-1.71 (m, 2H), 2.11-2.32 (m, 4H), 3.16 (d, + −2,4-pyrimidinediamine J = 3.6 Hz, 3H), 4.89 (m, J = 8.4 Hz, 1H), 7.36(d, J = 0.9 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.57 (m, 2H), 8.06 (d, J= 7.2 Hz, 1H), 8.20 (d, J = 0.9 Hz, 1H), 8.57 (t, J = 1.8 Hz, 1H), 9.68(s, 1180 (S)-N4- (1 -Benzylpyrrolidin-3-yl)-5-fluoro-N2- (4- 1H NMR(DMSO-d6): d 1.83 (m, 1H), 2.16 (m, 1H), 2.40 (dd, J = 5.1, + −morpholinophenyl)-2,4-pyrimidinediamine 9.3 Hz, 1H), 2.58 (m, 2H), 2.89(dd, J = 7.2, 9.3 Hz, 1H), 2.99 (t, J = 4.8 Hz, 4H), 3.58 (d, J = 1.8Hz, 2H), 3.72 (t, J = 4.8 Hz, 4H), 4.41 (m, 1H), 6.78 (d, J = 9.0 Hz,2H), 7.22 (m, 1H), 7.2 1181 (S)-N2-[4- (4-Acetylpiperazino)phenyl]-N4-(1-benzylpyrrolidin- 1H NMR (DMSO-d6): d 1.81-1.87 (m, 1H), 2.03 (s,3H), 2.14-2.23 (m, + − 3-yl)-5-fluoro-2,4-pyrimidinediamine 1H), 2.40(dd, J = 5.7, 9.6 Hz, 1H), 2.56 (m, 2H), 2.89 (dd, J = 7.2, 9.3 Hz, 1H),2.95 (t, J = 5.1 Hz, 2H), 3.02 (t, J = 5.1 Hz, 2H), 3.55 (m, 4H), 3.58(s, 2H), 4.41 (m, 1H), 6.81 (d, J = 9.0 1182 (S)-N4-(1-Benzylpyrrolidin-3-yl)-5-fluoro-N2-[4- (4- LCMS: ret. time: 1.17min.; purity: 95.41%; MS (m/e): 462.15 (MH+). − −methylpiperazino)phenyl]-2,4-pyrimidinediamine 1183 (S)-N4-(1-Benzylpyrrolidin-3-yl)-N2-[4- (4- 1H NMR (DMSO-d6): d 1.19 (t, J =7.2 Hz, 3H), 1.83 (m, 1H), 2.17 (m, + −ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4- 1H), 2.40 (dd, J = 5.1,9.0 Hz, 1H), 2.56 (m, 2H), 2.89 (dd, J = 7.2, 9.0 pyrimidinediamine Hz,1H), 2.98 (t, J = 5.1 Hz, 4H), 3.49 (t, J = 5.1 Hz, 4H), 3.58 (d, J =1.8 Hz, 2H), 4.05 (q, J = 7.2 Hz, 2H), 4.44 ( 1184 (S)-N4-(1-Benzylpyrrolidin-3-yl)-5-fluoro-N2- (3- LCMS: ret. time: 6.81 min.;purity: 100%; MS (m/e): 449 (MH+). + −morpholinophenyl)-2,4-pyrimidinediamine 1185 (S)-N2-[3-(4-Acetylpiperazino)phenyl]-N4- (benzylpyrrolidin-3- 1H NMR (DMSO-d6): d1.82-1.88 (m, 1H), 2.02 (s, 3H), 2.16-2.26 (m, + −yl)-5-fluoro-2,4-pyrimidinediamine 1H), 2.37 (dd, J = 5.7, 9.0 Hz, 1H),2.56 (m, 2H), 2.92 (dd, J = 6.9, 9.0 Hz, 1H), 3.03 (t, J = 5.1 Hz, 2H),3.10 (t, J = 5.1 Hz, 2H), 3.56 (m, 4H), 3.58 (s, 2H), 4.53 (m, 1H), 6.47(d, J = 8.4 1186 (S)-N4- (1-Benzylpyrrolidin-3-yl)-5-fluoro-N2-[3- (4-LCMS: ret. time: 2.79 min.; purity: 97.87%; MS (m/e): 462 (MH+). + −methylpiperazino)phenyl]-2,4-pyrimidinediamine 1187 (S)-N4-(1-Benzylpyrrolidin-3-yl)-N2-[3- (4- 1H NMR (DMSO-d6): d 1.18 (t, J =7.2 Hz, 3H), 1.82 (m, J = 6.5 Hz, + −ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4- 1H), 2.19 (m, 1H), 2.37(dd, J = 5.7, 9.0 Hz, 1H), 2.56 (m, 2H), 2.91 pyrimidinediamine (dd, J =7.2, 9.0 Hz, 1H), 3.06 (t, J = 5.1 Hz, 4H), 3.51 (t, J = 5.1 Hz, 4H),3.58 (s, 2H), 4.04 (q, J = 7.2 Hz, 2H), 4.55 ( 1188N4-Cyclobutyl-5-fluoro-N2-[3-chloro-4- (4- 1H NMR (DMSO-d6): d 1.61-1.73(m, 2H), 2.01-2.14 (m, 2H), 2.25- +methylpiperazino)phenyl]-2,4-pyrimidinediamine 2.33 (m, 2H), 2.29 (s,3H), 2.55 (m, 4H), 2.91 (t, 4H), 4.47 (m, J = 8.1 Hz, 1H), 7.03 (d, J =8.7 Hz, 1H), 7.43 (dd, J = 2.7, 9.0 Hz, 1H), 7.69 (d, J = 7.2 Hz, 1H),7.84 (d, J = 3.6 Hz, 1H), 8.07 1189 N4-(3,4-Dihydro-2H,4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-[3- 1H NMR(DMSO-d6): d 2.28 (s, 6H), 2.86 (d, J = 4.8 Hz, 3H), 2.92 (m, + +(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine Bis p- 2H), 3.13 (q, J= 10.8 Hz, 2H), 3.49 (m, 4H), 3.74 (d, J = 13.2 Hz, 2H), ToluenesulfonicAcid Salt 4.15 (t, J = 4.2 Hz, 2H), 6.66 (d, J = 7.8 Hz, 1H), 6.96 (d, J= 8.7 Hz, 1H), 7.08 (d, J = 8.4 Hz, 4H), 7.17 (m, 4H), 7. 1190 N4-(3,4-Dihydro-2H,4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-[3- 1H NMR(DMSO-d6): d 2.81 (d, J = 4.5 Hz, 3H), 3.08 (m, 4H), 3.48 (d, + +(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine Bis J = 11.7 Hz, 2H),3.55 (t, 2H), 3.72 (d, J = 11.7 Hz, 2H), 4.18 (t, J = 4.2 HydrogenChloride Salt Hz, 2H), 6.65 (d, J = 9.0 Hz, 1H), 6.74 (d, J = 8.1 Hz,1H), 7.15 (t, J = 8.1 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.41 1191N2-[3-Chloro-4- (4-methylpiperazino)phenyl]-N4-cyclohexyl-5- 1H NMR(DMSO-d6): d 1.14 (m, 1H), 1.33 (m, 4H), 1.63 (d, 1H), 1.74 + +fluoro-2,4-pyrimidinediamine (m, 2H), 1.90 (m, 2H), 2.21 (s, 3H), 2.45(m, 4H), 2.88 (t, 4H), 3.89 (m, 1H), 7.01 (d, J = 8.7 Hz, 1H), 7.24 (d,J = 7.8 Hz, 1H), 7.39 (dd, J = 2.4, 8.4 Hz, 1H), 7.81 (d, J = 3.9 Hz,1H), 8.0 1192 N2-[4-(4-Acetylpiperazino)phenyl]-N4-cyclobutyl-5-fluoro-2,4- 1H NMR(DMSO-d6): d 1.65-1.76 (m, 2H), 2.04 (s, 3H), 2.08-2.26 (m, +pyrimidinediamine Bis Hydrogen Chloride Salt 4H), 3.10 (t, 2H), 3.17 (t,2H), 3.58 (t, 4H), 4.43 (m, J = 7.8 Hz, 1H), 7.02 (d, J = 8.1 Hz, 2H),7.37 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 5.1 Hz, 1H), 9.10 (br, 1H), 10.02(br, 1H); 19F NMR (2 1193 N4-Cyclohexyl-5-fluoro-N2-[4-(4-methylpiperazino)phenyl]-2,4- 1H NMR (DMSO-d6): d 1.24 (m, 4H), 1.37(q, 1H), 1.62 (d, 1H), 1.76 + pyrimidinediamine Bis p-ToluenesulfonicAcid Salt (d, 2H), 1.85 (d, 2H), 2.28 (s, 6H), 2.86 (d, J = 3.9 Hz, 3H),2.92 (d, 2H), 3.15 (m, 2H), 3.52 (d, 2H), 3.80 (d, 3H), 7.00 (d, J = 9.3Hz, 2H), 7.09 (d, J = 7.8 Hz, 4H), 7.36 (d, J = 9.3 Hz, 1194N4-Cyclohexyl-5-fluoro-N2-[4- (4-methylpiperazino)phenyl]-2,4- 1H NMR(DMSO-d6): d 1.33 (m, 5H), 1.61 (d, 1H), 1.77 (d, 2H), 1.87 +pyrimidinediamine Bis Hydrogen Chloride Salt (d, 2H), 2.79 (d, J = 4.8Hz, 3H), 3.09 (m, 4H), 3.47 (d, 2H), 3.78 (d, 2H), 3.83 (m, 1H), 7.01(d, J = 9.0 Hz, 2H), 7.39 (d, J = 9.0 Hz, 2H), 8.10 (d, J = 5.4 Hz, 1H),9.08 (d, J = 8.1 Hz, 1H) 1195 N2-[3-Chloro-4-(4-methylpiperazino)phenyl]-N4-cyclopentyl-5- 1H NMR (DMSO-d6): d 1.55(m, 4H), 1.71 (m, 2H), 1.98 (m, 2H), 2.31 + fluoro-2,4-pyrimidinediamine(s, 3H), 2.57 (m, 4H), 2.91 (t, 4H), 4.30 (q, J = 6.9 Hz, 1H), 7.03 (d,J = 8.7 Hz, 1H), 7.36 (d, J = 6.9 Hz, 1H), 7.43 (dd, J = 2.7, 9.0 Hz,1H), 7.82 (d, J = 3.9 Hz, 1H), 8.07 (d, J = 2.4 Hz, 1196 N2-[3-Chloro-4-(4-methylpiperazino)phenyl]-N4- (3-cyclopropyl- 1H NMR (DMSO-d6): d 0.69(m, 2H), 0.91 (m, 2H), 1.87 (m, 1H), 2.22 +1H-pyrazol-5-yl)-5-fluoro-2,4-pyrimidinediamine (s, 3H), 2.46 (m, 4H),2.90 (t, 4H), 6.31 (br, 1H), 7.04 (d, J = 9.0 Hz, 1H), 7.51 (br, 1H),7.79 (s, 1H), 8.02 (s, 1H), 9.14 (br, 1H), 9.52 (br, 1H), 12.07 (br,1H); 19F NMR (282 MHz, DMSO 1197 N2-[3-Chloro-4-(4-methylpiperazino)phenyl]-N4- (3,4-dihydro- 1H NMR (DMSO-d6): d 2.21(s, 3H), 2.45 (t, 4H), 2.88 (t, 4H), 3.39 (m, + +2H,4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 2H), 4.09(t, J = 4.2 Hz, 2H), 6.53 (s, 1H), 6.94 (d, J = 8.7 Hz, 1H), 7.01 (d, J= 8.7 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.46 (dd, J = 2.7, 8.7 Hz, 1H),7.84 (d, J = 2.7 Hz, 1H), 8.04 (d, 1198 N2-[3-Chloro-4-(4-methylpiperazino)phenyl]-N4-cyclobutyl-5- 1H NMR (DMSO-d6): d1.67-1.76 (m, 2H), 2.11-2.18 (m, 2H), 2.25- +fluoro-2,4-pyrimidinediamine Bis Hydrogen Chloride Salt 2.31 (m, 2H),2.82 (d, J = 4.5 Hz, 3H), 3.02-3.20 (m, 4H), 3.35 (m, 2H), 3.48 (m, 2H),4.44 (m, J = 7.5 Hz, 1H), 7.18 (d, J = 8.7 Hz, 1H), 7.40 (dd, J = 2.4,8.7 Hz, 1H), 7.97 (d, J = 2.1 Hz, 1H), 1199 N2-[3-Chloro-4-(4-methylpiperazino)phenyl]-N4-cyclohexyl-5- 1H NMR (DMSO-d6): d 1.17(m, 1H), 1.36 (m, 4H), 1.63 (d, 1H), 1.78 + +fluoro-2,4-pyrimidinediamine Bis Hydrogen Chloride Salt (m, 2H), 1.86(m, 2H), 2.83 (d, J = 4.8 Hz, 3H), 3.00-3.20 (m, 4H), 3.34 (m, 2H), 3.48(m, 2H), 3.87 (m, 1H), 7.16 (d, J = 8.7 Hz, 1H), 7.36 (dd, J = 2.4, 9.0Hz, 1H), 7.96 (d, J = 2.4 Hz, 1H) 1200N4-Cyclopentyl-5-fluoro-N2-[3-methyl-4- (4- LCMS: ret. time: 9.70 min.;purity: 89.34%; MS (m/e): 385 (MH+). +methylpiperazino)phenyl]-2,4-pyrimidinediamine 1201N4-Cyclohexyl-5-fluoro-N2-[3-methyl-4- (4- LCMS: ret. time: 11.34 min.;purity: 94.34%; MS (m/e): 399.24 (MH+). + +methylpiperazino)phenyl]-2,4-pyrimidinediamine 1202 N4-(3-Cyclopropyl-1H-pyrazol-5-yl)-5-fluoro-N2-[3-methyl-4- (4- LCMS: ret.time: 10.35 min.; purity: 96.72%; MS (m/e): 423 (MH+). + +methylpiperazino)phenyl]-2,4-pyrimidinediamine 1203 N4-(3,4-Dihydro-2H,4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-[3- LCMS: ret.time: 10.77 min.; purity: 93.79%; MS (m/e): 451 (MH+). + + methyl-4-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine 12045-Fluoro-N4-isopropyl-N2-[4- (4-methylpiperazino)phenyl]-2,4- LCMS: ret.time: 3.64 min.; purity: 95.29%; MS (m/e): 345 (MH+). +pyrimidinediamine 1205 N2-[3-Chloro-4-(4-methylpiperazino)phenyl]-5-fluoro-N4- LCMS: ret. time: 5.14 min.;purity: 92.47%; MS (m/e): 379 (MH+). + isopropyl-2,4-pyrimidinediamine1206 5-Fluoro-N4-isopropyl-N2-[3-methyl-4- (4- LCMS: ret. time: 1.99min.; purity: 93.17%; MS (m/e): 359 (MH+). + −methylpiperazino)phenyl]-2,4-pyrimidinediamine 1207N4-Cyclobutyl-5-fluoro-N2-[4- (4-methylpiperazino)-3- LCMS: ret. time:15.09 min.; purity: 94.19%; MS (m/e): 425 (MH+). +trifluoromethylphenyl]-2,4-pyrimidinediamine 1208N4-Cyclopentyl-5-fluoro-N2-[4- (4-methylpiperazino)-3- LCMS: ret. time:15.32 min.; purity: 92.83%; MS (m/e): 439.30 (MH+). +trifluoromethylphenyl]-2,4-pyrimidinediamine 1209N4-Cyclohexyl-5-fluoro-N2-[4- (4-methylpiperazino)-3- LCMS: ret. time:15.74 min.; purity: 95.26%; MS (m/e): 453 (MH+). +trifluoromethylphenyl]-2,4-pyrimidinediamine 12105-Fluoro-N4-isopropyl-N2-[4- (4-methylpiperazino)-3- LCMS: ret. time:7.29 min.; purity: 88.24%; MS (m/e): 413.05 (MH+). +trifluoromethylphenyl]-2,4-pyrimidinediamine 1211 N4-(3-Cyclopropyl-1H-pyrazol-5-yl)-5-fluoro-N2-[ (4- LCMS: ret. time: 8.27min.; purity: 94.19%; MS (m/e): 477 (MH+). +methylpiperazino)-3-trifluoromethylphenyl]-2,4- pyrimidinediamine 12122-chloro-5-fluoro-N4- (1,2,2,6,6-pentamethylpiperidin-4-yl)-4- LCMS:ret. time: 9.57 min.; purity: 90.78%; MS (m/e): 301.19 (MH+). −pyrimidineamine 1213 2-chloro-N4-(1-ethoxycarbonylpiperidin-4-yl)-5-fluoro-4- LCMS: ret. time: 10.29min.; purity: 94%; MS (m/e): 303.04 (MH+). − pyrimidineamine 12145-Fluoro-N4-isopropyl-N2-[3- (4-methylpiperazino)phenyl]-2,4- LCMS: ret.time: 4.63 min.; purity: 97.16%; MS (m/e): 345.41 (MH+). −pyrimidinediamine 1215 N4-tert-Butyl-5-fluoro-N2-[4-(4-methylpiperazino)phenyl]-2,4- LCMS: ret. time: 2.80 min.; purity:97.03%; MS (m/e): 359 (MH+). − pyrimidinediamine 1216N4-tert-Butyl-5-fluoro-N2-[3- (4-methylpiperazino)phenyl]-2,4- LCMS:ret. time: 7.81 min.; purity: 94.56%; MS (m/e): 359.23 (MH+). −pyrimidinediamine 1217 N4-tert-Butyl-N2-[3-chloro-4-(4-methylpiperazino)phenyl]-5- LCMS: ret. time: 10.53 min.; purity:93.25%; MS (m/e): 393 (MH+). + fluoro-2,4-pyrimidinediamine 1218N4-tert-Butyl-5-fluoro-N2-[3-methyl-4- (4- LCMS: ret. time: 4.35 min.;purity: 87.23%; MS (m/e): 373.26 (MH+). +methylpiperazino)phenyl]-2,4-pyrimidinediamine 1219 5-Fluoro-N2-[4-(4-methylpiperazino)phenyl]-N4- (1,2,2,6,6- LCMS: ret. time: 1.30 min.;purity: 95.14%; MS (m/e): 456.63 (MH+). −pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine 1220N4-Cyclobutyl-5-fluoro-N2-[3-methyl-4- (4- LCMS: ret. time: 9.16 min.;purity: 93.00%; MS (m/e): 371.26 (MH+). +methylpiperazino)phenyl]-2,4-pyrimidinediamine 1221 5-Fluoro-N2-[3-(4-methylpiperazino)phenyl]-N4- (1,2,2,6,6- LCMS: ret. time: 1.40, 1.71min.; purity: 95%; MS (m/e): 456.30 (MH+). −pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine 1222 N2-[3-Chloro-4-(4-methylpiperazino)phenyl]-5-fluoro-N4- LCMS: ret. time: 1.44, 1.74min.; purity: 97%; MS (m/e): 490.11 (MH+). −(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine 12235-Fluoro-N2-[3-methyl-4- (4-methylpiperazino)phenyl]-N4- LCMS: ret.time: 1.46, 2.03 min.; purity: 100%; MS (m/e): 470.29 +(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine (MH+). 12245-Fluoro-N4- (1,2,2,6,6-pentamethylpiperidin-4-yl)-N2-[3- LCMS: ret.time: 1.46, 2.70 min.; purity: 97%; MS (m/e): 524.23 (MH+). −trifluoromethyl-4- (4-methylpiperazino)phenyl]-2,4- pyrimidinediamine1225 N4- (1-Ethoxycarbonylpiperidin-4-yl)-5-fluoro-N2-[4- (4- LCMS: ret.time: 6.13 min.; purity: 95.45%; MS (m/e): 458 (MH+). +methylpiperazino)phenyl]-2,4-pyrimidinediamine 1226 N4-(1-Ethoxycarbonylpiperidin-4-yl)-5-fluoro-N2-[3- (4- LCMS: ret. time:9.94 min.; purity: 97%; MS (m/e): 458.27 (MH+). +methylpiperazino)phenyl]-2,4-pyrimidinediamine 1227 N2-[3-Chloro-4-(4-methylpiperazino)phenyl]-N4- (1- LCMS: ret. time: 14.71 min.; purity:98.79%; MS (m/e): 492 (MH+). +ethoxycarbonylpiperidin-4-yl)-5-fluoro-2,4-pyrimidinediamine 1228 N4-(1-Ethoxycarbonylpiperidin-4-yl)-5-fluoro-N2-[3-methyl-4- LCMS: ret.time: 9.26 min.; purity: 97.16%; MS (m/e): 472 (MH+). +(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine 1229 N4-(1-Ethoxycarbonylpiperidin-4-yl)-5-fluoro-N2-[4- (4- LCMS: ret. time:15.48 min.; purity: 97.96%; MS (m/e): 526 (MH+). +methylpiperazino)-3-trifluoromethylphenyl]-2,4- pyrimidinediamine 1230N4-Cyclobutyl-N2-[2- (4-ethylpiperazino)pyrid-5-yl]-5-fluoro-2,4- LCMS:ret. time: 5.52 min.; purity: 94.98%; MS (m/e): 372 (MH+). +pyrimidinediamine 1231 N4-Cyclopentyl-N2-[2-(4-ethylpiperazino)pyrid-5-yl]-5-fluoro- LCMS: ret. time: 6.27 min.;purity: 90.61%; MS (m/e): 386.36 (MH+). + 2,4-pyrimidinediamine 1232N4-Cyclohexyl-N2-[2- (4-ethylpiperazino)pyrid-5-yl]-5-fluoro- LCMS: ret.time: 6.83 min.; purity: 97.62%; MS (m/e): 400 (MH+). +2,4-pyrimidinediamine 1233 N4-tert-Butyl-5-fluoro-N2-[4-(4-methylpiperazino)-3- LCMS: ret. time: 15.37 min.; purity: 96.00%; MS(m/e): 427 (MH+). + trifluoromethylphenyl]-2,4-pyrimidinediamine 1234N2-[2- (4-Ethylpiperazino)pyrid-5-yl]-5-fluoro-N4-isopropyl-2,4- LCMS:ret. time: 1.44, 1.80 min.; purity: 96%; MS (m/e): 360.28 (MH+). +pyrimidinediamine 1235 N4-Cyclobutyl-5-fluoro-N2-[3-hydroxymethyl-4- (4-LCMS: ret. time: 1.82 min.; purity: 90%; MS (m/e): 387.14 (MH+). −methylpiperazino)phenyl]-2,4-pyrimidinediamine 1236 N4-tert-Butyl-N2-[2-(4-ethylpiperazino)pyrid-5-yl]-5-fluoro-2,4- LCMS: ret. time: 4.27 min.;purity: 100%; MS (m/e): 374.18 (MH+). − pyrimidinediamine 1237 N2-[2-(4-Ethylpiperazino)pyrid-5-yl]-5-fluoro-N4- (1,2,2,6,6- LCMS: ret. time:1.27 min.; purity: 99.58%; MS (m/e): 471.73 (MH+). −pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine 1238 N4-(1-Ethoxycarbonylpiperidin-4-yl)-N2-[2- (4- LCMS: ret. time: 7.03 min.;purity: 94.74%; MS (m/e): 473 (MH+). −ethylpiperazino)pyrid-5-yl]-5-fluoro-2,4-pyrimidinediamine 1239N4-Cyclobutyl-5-fluoro-N2-[2- (4-methylpiperazino)-3- LCMS: ret. time:9.65 min.; purity: 97.08%; MS (m/e): 372.11 (MH+). −methylpyrid-5-yl]-2,4-pyrimidinediamine 1240N4-Cyclopentyl-5-fluoro-N2-[2- (4-methylpiperazino)-3- LCMS: ret. time:10.50 min.; purity: 91.36%; MS (m/e): 385.85 (MH+). +methylpyrid-5-yl]-2,4-pyrimidinediamine 1241N4-Cyclohexyl-5-fluoro-N2-[2- (4-methylpiperazino)-3- LCMS: ret. time:9.22 min.; purity: 93.96%; MS (m/e): 400.11 (MH+). +methylpyrid-5-yl]-2,4-pyrimidinediamine 12425-Fluoro-N4-isopropyl-N2-[2- (4-methylpiperazino)-3- LCMS: ret. time:4.21 min.; purity: 91.67%; MS (m/e): 360.15 (MH+). +methylpyrid-5-yl]-2,4-pyrimidinediamine 1243N4-Cyclobutyl-5-fluoro-N2-[3-hydroxymethyl-4- (4- LCMS: ret. time: 1.43,1.85 min.; purity: 94%; MS (m/e): 387.05 (MH+). +methylpiperazino)phenyl]-2,4-pyrimidinediamine Bishydrogen chloride salt1244 5-Fluoro-N2-[2- (4-methylpiperazino)-3-methylpyrid-5-yl]-N4- LCMS:ret. time: 7.05 min.; purity: 95.56%; MS (m/e): 471.26 (MH+). −(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine 1245N4-Cyclobutyl-5-fluoro-N2-[2- (4-methylpiperazino)-4- LCMS: ret. time:9.37 min.; purity: 92.45%; MS (m/e): 371.99 (MH+). −methylpyrid-5-yl]-2,4-pyrimidinediamine 1246N4-Cyclopentyl-5-fluoro-N2-[2- (4-methylpiperazino)-4- LCMS: ret. time:10.12 min.; purity: 95.69%; MS (m/e): 386.09 (MH+). −methylpyrid-5-yl]-2,4-pyrimidinediamine 1247N4-Cyclohexyl-5-fluoro-N2-[2- (4-methylpiperazino)-4- LCMS: ret. time:10.35 min.; purity: 92.30%; MS (m/e): 400.13 (MH+). +methylpyrid-5-yl]-2,4-pyrimidinediamine 12485-Fluoro-N4-isopropyl-N2-[2- (4-methylpiperazino)-4- LCMS: ret. time:6.77 min.; purity: 84.20%; MS (m/e): 359.97 (MH+). −methylpyrid-5-yl]-2,4-pyrimidinediamine 1249 5-Fluoro-N2-[2-(4-methylpiperazino)-4-methylpyrid-5-yl]-N4- LCMS: ret. time: 1.48, 2.77min.; purity: 98%; MS (m/e): 471.22 (MH+). −(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pyrimidinediamine 12505-Fluoro-N4- (1-hydroxymethylcyclopent-1-yl)-N2-[3-methyl-4- LCMS: ret.time: 11.16 min.; purity: 99.47%; MS (m/e): 415.57 (MH+). +(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine 1251 N4-(5-Amino-1,2,4-triazol-3-yl)-5-fluoro-N2-[3- (N- LCMS: purity: 93.2%; MS(m/e): 374.52 (MH+, 100). + methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 1252 N4- (3-Amino-1,2,4-triazol-5-yl)-N2-(3,5-dimethylphenyl)-5- ¹H NMR (DMSO): d 8.71 (d, 1H, J = 4.5 Hz), 7.75(s, 1H), 7.53 (s, 2H), − fluoro-2,4-pyrimidinediamine 7.21 (s, 1H),6.61-6.74 (m, 2H), 5.83 (bs, 2H), 2.43 (s, 6H); LCMS: purity: 88.8%; MS(m/e): 315.24 (MH+, 100). 1253 N4- (5-Amino-1,2,4-triazol-3-yl)-N2-(3-chloro-4- LCMS: purity: 92.8%; MS (m/e): 351.09 (MH+, 100). −methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 1254 N4-(5-Amino-1,2,4-triazol-3-yl)-N2- (3,4-dichlorophenyl)-5- LCMS: purity:93.2%; MS (m/e): 355.23 (MH+, 100). − fluoro-2,4-pyrimidinediamine 1255N4- (5-Amino-1,2,4-triazol-3-yl)-5-fluoro-N2- (indazol-6-yl)-2,4- LCMS:purity: 94.3%; MS (m/e): 327.14 (MH+, 100). + + pyrimidinediamine 1256N4-[ (2,3-Dihydro-1,4-benzodioxan-2-yl)methyl]-N2- (3,5- ¹H NMR (DMSO):d 10.09 (bs, 1H), 9.12 (bs, 1H), 8.13 (d, 1H, J = 5.1 +dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine Hz), 7.17 (s, 2H),6.74-6.87 (m, 5H), 4.29-4.50 (m, 2H), 3.98 (dd, 1H, 6.3, 11.4 Hz),3.59-3.80 (m, 2H), 2.23 (s, 6H); LCMS: purity: 97.8%; MS (m/e): 379.14(M-, 100). 1257 N4-[(2,3-Dihydro-1,4-benzodioxan-2-yl)methyl]-5-fluoro-N2-[3- LCMS: purity:97.4%; MS (m/e): 438.13 (M-, 100). +(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- pyrimidinediamine 1258N4-[ (2,3-Dihydro-1,4-benzodioxan-2-yl)methyl]-N2- (3,5- ¹H NMR (DMSO):d 10.13 (s, 1H), 9.05 (bs, 1H), 8.19 (d, 1H, J = 4.8 +dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine Hz), 6.79-6.86 (m, 6H),6.24 (m, 1H), 4.29-4.49 (m, 2H), 4.00 (dd, 1H, 6.9, 11.4 Hz), 3.62-3.79(m, 8H); LCMS: purity: 96.7%; MS (m/e): 411.10 (M-, 100). 1259 N2-(3-Chloro-4-methoxyphenyl)-N4-[ (2,3-dihydro-1,4- ¹H NMR (DMSO): d 10.22(s, 1H), 9.11 (bs, 1H), 8.12 (d, 1H, J = 5.1 +benzodioxan-2-yl)methyl]-5-fluoro-2,4-pyrimidinediamine Hz), 7.70 (d,1H, J = 2.4 Hz), 7.35 (dd, 1H, J = 2.7, 9.0 Hz), 7.08 (d, 1H, J = 9.0Hz), 6.78-6.87 (m, 4H), 4.28-4.49 (m, 2H), 3.99 (dd, 1H, 6.9, 11.7 Hz),3.59-3.84 (m, 5H); LCMS: purity 1260 N4-[(2,3-Dihydro-1,4-benzodioxan-2-yl)methyl]-5-fluoro-N2- LCMS: purity:95.0%; MS (m/e): 391.10 (M-, 100). +(indazol-6-yl)-2,4-pyrimidinediamine 1261 N4-(3,4-Dichlorophenyl)-5-fluoro-N2- (4- LCMS: purity: 100%; MS (m/e):405.09 (M-, 100). − methoxycarbonylphenyl)-2,4-pyrimidinediamine 1262N2-[4- (N-Carboxymethyleneamino)carbonylphenyl]-N4- (3,4- LCMS: purity:100%; MS (m/e): 450.11 (M-) −dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine 1263 (S)-5-Fluoro-N2-(4-methoxycarbonylphenyl)-N4- (2-methyl-3- ¹H NMR (DMSO): d 10.74 (s,1H), 9.95 (s, 1H), 9.80 (s, 1H), 8.18 (d, +oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 1H, J = 4.2 Hz),7.20-7.79 (m, 6H), 6.96 (d, 1H, J = 9.3 Hz), 4.66 (q, 1H, J = 6.6 Hz),3.78 (s, 3H), 1.45 (d, 3H, J = 6.6 Hz); LCMS: purity: 96.8%; MS (m/e):422.12 (M-, 100). 1264 (S)-N2-[4-(N-Carboxymethyleneamino)carbonylphenyl]-5- ¹H NMR (DMSO): d 10.75 (s,1H), 9.88 (s, 1H), 9.63 (m, 1H), 8.19 (d, − fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- 1H, J = 4.5 Hz),7.19-7.75 (m, 6H), 6.98 (d, 1H, J = 8.7 Hz), 4.67 (q, pyrimidinediamine1H, J = 6.9 Hz), 3.89 (d, 1H, 5.7 Hz), 1.44 (d, 3H, J = 6.9 Hz); LCMS:purity: 91.2%; MS (m/e): 465.21 (M-, 100). 1265 (R)-N2-(4-Aminocarbonylphenyl)-5-fluoro-N4- (2-methyl-3-oxo- LCMS: purity:95.5%; MS (m/e): 407.17 (M-, 100). +2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 1266 (R)-5-Fluoro-N2-(4-methoxycarbonylphenyl)-N4- (2-methyl-3- ¹H NMR (DMSO): d 10.74 (s,1H), 9.95 (s, 1H), 9.80 (s, 1H), 8.18 (d, +oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 1H, J = 4.2 Hz),7.20-7.79 (m, 6H), 6.96 (d, 1H, J = 9.3 Hz), 4.66 (q, 1H, J = 6.6 Hz),3.78 (s, 3H), 1.45 (d, 3H, J = 6.6 Hz); LCMS: purity: 98.5%; MS (m/e):422.17 (M-, 100). 1267 (R)-N2-[4-(N-Carboxymethyleneamino)carbonylphenyl]-5- ¹H NMR (DMSO): d 10.75 (s,1H), 9.88 (s, 1H), 9.63 (m, 1H), 8.19 (d, − fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- 1H, J = 4.5 Hz),7.19-7.75 (m, 6H), 6.98 (d, 1H, J = 8.7 Hz), 4.67 (q, pyrimidinediamine1H, J = 6.9 Hz), 3.89 (d, 1H, 5.7 Hz), 1.44 (d, 3H, J = 6.9 Hz); LCMS:purity: 87.5%; MS (m/e): 465.21 (M-, 100). 1268 N2,N4-Bis[4-(N-tert-butoxycarbonylamino)methylenephenyl]-5- LCMS: purity: 100%; MS(m/e): 537.34 (M-, 100). + fluoro-2,4-pyrimidinediamine 1269 N2,N4-Bis(4-aminomethylenephenyl)-5-fluoro-2,4- 1H NMR (DMSO): d 9.25 (bs, 1H),9.09 (bs, 1H), 8.05 (d, 1H, J = 2.4 + + + + pyrimidinediamine Hz), 7.69(d, 2H, J = 8.7 Hz), 7.56 (d, 2H, J = 8.7 Hz), 7.04-7.40 (m, 4H), 3.67(s, 3H), 3.61 (s, 3H), 3.35 (bs, 4H); LCMS: purity: 95.5%; MS (m/e):337.18 (M-, 100) 1270 N4- (3,4-Dichlorophenyl)-5-fluoro-N2-[4- (N- ¹HNMR (DMSO): d 10.21 (s, 2H), 8.33 (m, 1H), 8.33 (d, 1H, J = 4.5 +methoxycarbonylmethyleneamino)carbonylphenyl]-2,4- Hz), 8.10 (d, 1H, J =2.4 Hz), 7.59-7.83 (m, 6H), 3.99 (m, 2H), 3.65 (s, pyrimidinediamine3H); LCMS: purity: 100%; MS (m/e): 462.11 (M-, 100). 1271(S)-5-Fluoro-N2-[4- (N- ¹H NMR (DMSO): d 10.77 (s, 1H), 9.93 (bs, 1H),8.77 (m, 1H), 8.20 (d, + −methoxycarbonylmethyleneamino)carbonylphenyl]-N4- (2- 1H, J = 4.5 Hz),7.21-7.75 (m, 6H), 6.97 (d, 1H, J = 8.4 Hz), 4.66 (q,methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- 1H, J = 6.6 Hz), 3.97 (m,2H), 3.64 (s, 3H), 1.44 (d, 3H, J = 6.6 Hz); pyrimidinediamine LCMS:purity: 96.7%; MS (m/e): 481.16 (MH+, 1272 (R)-5-Fluoro-N2-[4- (N- ¹HNMR (DMSO): d 10.77 (s, 1H), 9.93 (bs, 1H), 8.77 (m, 1H), 8.20 (d, + −methoxycarbonylmethyleneamino)carbonylphenyl]-N4- (2- 1H, J = 4.5 Hz),7.21-7.75 (m, 6H), 6.97 (d, 1H, J = 8.4 Hz), 4.66 (q,methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- 1H, J = 6.6 Hz), 3.97 (m,2H), 3.64 (s, 3H), 1.44 (d, 3H, J = 6.6 Hz); pyrimidinediamine LCMS:purity: 100%; MS (m/e): 481.39 (MH+, 1273 N2,N4-Bis[3-(N-tert-butoxycarbonylamino)methylenephenyl]-5- ¹H NMR (DMSO): d 9.43(s, 1H), 9.22 (s, 1H), 9.08 (d, 1H, J = 3.6 Hz), +fluoro-2,4-pyrimidinediamine 7.24-7.72 (m, 7H), 7.15 (t, 1H, J = 7.8Hz), 6.94 (d, 1H, J = 7.5 Hz), 6.78 (d, 1H, J = 7.5 Hz), 4.08 (m, 4H),1.39 (s, 18H); LCMS: purity: 95.8%; MS (m/e): 537.16 (M-, 100). 1274N2,N4-Bis (3-aminomethylenephenyl)-5-fluoro-2,4- ¹H NMR (DMSO): d 9.24(s, 1H), 8.35 (s, 1H), 8.01-8.07 (m, 2H), 6.73- + + pyrimidinediamine7.71 (m, 7H), 3.69 (s, 2H), 3.61 (s, 2H); LCMS: purity: 100%; MS (m/e):337.21 (M-, 100). 1275 N2-[3-(N-tert-Butoxycarbonylamino)methylenephenyl]-N4- (3,4- LCMS: purity:93.5%; MS (m/e): 476.19 (M-, 100). + +dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine 1276 (S)-N2-[3-(N-tert-Butoxycarbonylamino)methylenephenyl]-5- ¹H NMR (DMSO): d 10.61(s, 1H), 9.30 (s, 1H), 9.04 (s, 1H), 8.03 (d, + + fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- 1H, J = 3.9 Hz),7.22-7.54 (m, 5H), 7.10 (t, 1H, J = 7.5 Hz), 6.92 (d, pyrimidinediamine1H, J = 7.5 Hz), 4.64 (q, 1H, J = 6.6 Hz), 4.01 (m, 2H), 1.44 (d, 3H, J= 6.6 Hz), 1.39 (s, 9H); LCMS: purity: 95.1 1277 (R)-N2-[3-(N-tert-Butoxycarbonylamino)methylenephenyl]-5- ¹H NMR (DMSO): d 10.61(s, 1H), 9.30 (s, 1H), 9.04 (s, 1H), 8.03 (d, + + fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl) 1H, J = 3.9 Hz), 7.22-7.54(m, 5H), 7.10 (t, 1H, J = 7.5 Hz), 6.92 (d, 1H, J = 7.5 Hz), 4.64 (q,1H, J = 6.6 Hz), 4.01 (m, 2H), 1.44 (d, 3H, J = 6.6 Hz), 1.39 (s, 9H);LCMS: purity: 92.2 1278 N2- (3-Aminomethylenephenyl)-N4-(3,4-dichlorophenyl)-5- ¹H NMR (DMSO): d 9.60 (bs, 1H), 9.31 (s, 1H),8.16 (d, 1H, J = 3.6 + + fluoro-2,4-pyrimidinediamine Hz), 8.12 (d, 1H,J = 2.7 Hz), 6.81-7.88 (m, 6H), 3.70 (s, 2H); LCMS: purity: 96.4%; MS(m/e): 376.11 (M-, 100). 1279 (S)-N2-(3-Aminomethylenephenyl)-5-fluoro-N4- (2-methyl-3- ¹H NMR (DMSO): d 9.30(s, 1H), 9.08 (s, 1H), 8.05 (m, 1H), 6.76-7.60 + +oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine (m, 8H), 4.63 (q,1H, J = 6.9 Hz), 3.64 (s, 2H), 1.43 (d, 3H, J = 6.9 Hz); LCMS: purity:100%; MS (m/e): 393.20 (M-, 100). 1280 (R)-N2-(3-Aminomethylenephenyl)-5-fluoro-N4- (2-methyl-3- ¹H NMR (DMSO): d 9.30(s, 1H), 9.08 (s, 1H), 8.05 (m, 1H), 6.76-7.60 + +oxo-2H,4H-benz[1,4]oxazin-6-yl-2,4-pyrimidinediamine (m, 8H), 4.63 (q,1H, J = 6.9 Hz), 3.64 (s, 2H), 1.43 (d, 3H, J = 6.9 Hz); LCMS: purity:98.5%; MS (m/e): 393.20 (M-, 100). 1281 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- ¹H NMR (DMSO):d 10.69 (s, 1H), 10.18 (bs, 1H), 8.25 (d, 1H, J = 4.5 + + − [3-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine Hz), 8.12-8.17 (m, 2H), 7.73(d, 1H, J = 8.1 Hz), 7.62 (d, 1H, J = 7.5 Hz), 7.21-7.39 (m, m, 4H),6.76 (d, 1H, J = 8.4 Hz), 1.38 (s, 6H); LCMS: purity: 100%; MS (m/e):445.14 (M-, 100). 1282 (S)-5-Fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)- ¹H NMR (DMSO): d 10.69 (s,1H), 9.98 (bs, 2H), 8.22 (d, 1H, J = 2.4 + + − N2-[3-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine Hz), 8.16 (m, 1H), 7.21-7.75(m, 6H), 6.78 (d, 1H, J = 8.4 Hz), 4.62 (q, 1H, J = 6.9 Hz), 1.42 (d,3H, J = 6.9 Hz); LCMS: purity: 97.3%; MS (m/e): 431.15 (M-, 100). 1283(R)-5-Fluoro-N4- (2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)- ¹H NMR(DMSO): d 10.69 (s, 1H), 9.98 (bs, 2H), 8.22 (d, 1H, J = 2.4 + + −N2-[3- (oxazol-2-yl)phenyl]-2,4-pyrimidinediamine Hz), 8.16 (m, 1H),7.21-7.75 (m, 6H), 6.78 (d, 1H, J = 8.4 Hz), 4.62 (q, 1H, J = 6.9 Hz),1.42 (d, 3H, J = 6.9 Hz); LCMS: purity: 94.9%; MS (m/e): 431.15 (M-,100). 1284 N4- (2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2-¹H NMR (DMSO): d 12.05 (s, 1H), 10.05 (s, 1H), 9.95 (s, 1H), 8.27 + + −[3- (oxazol-2-yl)phenyl]-2,4-pyrimidinediamine (m, 1H), 8.25 (d, 1H, J =4.5 Hz), 8.14 (s, 1H), 7.32-7.75 (m, 6H), 7.13 (d, 1H, J = 9.0 Hz);LCMS: purity: 98.0%; MS (m/e): 453.12 (M-, 100). 1285 N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2- LCMS: purity:87.8%; MS (m/e): 417.18 (M-, 100). + + − [3-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 1286 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- ¹H NMR (DMSO):d 10.71 (s, 1H), 9.91 (bs, 1H), 8.73 (m, 1H), 1.19 (d, + + − + [4-(N-methoxycarbonylmethyleneamino)carbonylphenyl]-2,4- 1H, J = 4.5 Hz),7.19-7.74 (m, 6H), 6.94 (d, 1H, J = 8.4 Hz), 3.97 (m, pyrimidinediamine2H), 3.64 (s, 3H), 1.38 (s, 6H); LCMS: purity: 97.5%; MS (m/e): 493.22(M-, 100). 1287 N4- (4-N-tert-Butoxycarbonylamino-3,4-dihydro-2H-1-LCMS: purity: 89.3%; MS (m/e): 517.26 (M-, 100). + −benzopyran-6-yl)-5-fluoro-N2-[3- (oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 1288 N4-(4-N-tert-Butoxycarbonylamino-3,4-dihydro-2H-1- LCMS: purity: 96.6%; MS(m/e): 516.90 (M-, 100). + + + benzopyran-6-yl)-5-fluoro-N2-[4-(oxazol-5-yl)phenyl]-2,4- pyrimidinediamine 1289 N4-(4-N-tert-Butoxycarbonylamino-3,4-dihydro-2H-1- LCMS: purity: 87.2%; MS(m/e): 517.54 (M-, 100). + + benzopyran-6-yl)-5-fluoro-N2-[4-(oxazol-2-yl)phenyl]-2,4- pyrimidinediamine 1290 5-Fluoro-N4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)- LCMS: purity: 100%; MS(m/e): 518.16 (M-, 100). + + − N2-[4-(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 1291 5-Fluoro-N4-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)- ¹H NMR (DMSO): d 10.40 (s,1H), 10.25 (s, 1H), 8.26 (d, 1H, J = 4.8 + + − N2-[4-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine Hz), 8.15 (s, 1H), 7.65-7.83(m, 4H), 7.50 (d, 1H, J = 2.7 Hz), 7.40 (dd, 1H, J 2.7, 8.4 Hz), 7.32(s, 1H), 6.81 (d, 1H, J = 8.7 Hz), 4.59 (t, 1H, J = 5.1 Hz), 4.20-4.24(m, 2H), 1.70-2.1 1292(R,S)-N4-[4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl]-5- 1H NMR (DMSO-d6):d 9.25 (s, 1H), 9.19 (s, 1H), 8.35 (s, 1H), 8.05 + + − fluoro-N2-[3-(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine (d, J = 3.6 Hz, 1H), 7.99 (m,1H), 7.20-7.63 (m, 5H), 6.62 (d, J = 8.7 Hz, 1H), 3.86-4.20 (m, 3H),1.75-2.0 (m, 2H); LCMS: purity: 91.8%; MS (m/e): 419.3 (MH+). 1293(R,S)-N4-[4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl]-5- LCMS: purity:98.0%; MS (m/e): 419.2 (MH+). + fluoro-N2-[4-(oxazol-5-yl)phenyl]-2,4-pyrimidinediamine 1294(R,S)-N4-[4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl]-5- LCMS: purity:93.5%; MS (m/e): 419.3 (MH+). + fluoro-N2-[4-(oxazol-2-yl)phenyl]-2,4-pyrimidinediamine 1295 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 10.73 (s, 1H), 9.97 (s, 1H), 9.87 (s, 1H), 8.53 + + −[4-[N- (N- (m, 1H), 8.19 (d, J = 4.2 Hz, 1H), 7.66-7.83 (m, 5H),7.24-7.27 (m, 2H),methylamino)carbonylmethylene]aminocarbonylphenyl]-2,4- 6.94 (d, J = 8.4Hz, 1H), 3.78 (d, J = 5.7 Hz, 2H), 2.58 (d, J = 4.5 Hz,pyrimidinediamine 3H), 1.41 (s, 6H); purity 98.2%; MS (m 1296(S)-5-Fluoro-N2-[4-[N- (N- 1H NMR (DMSO-d6): d 10.85 (s, 1H), 10.21 (s,1H), 9.98 (s, 1H), 8.58 + + −methylamino)carbonylmethylene]aminocarbonylphenyl]-N4- (2- (m, 1H), 8.22(d, J = 4.5 Hz, 1H), 7.68-7.79 (m, 6H), 7.43 (m, 1H), 7.23methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- (m, 1H), 6.95 (d, J = 9.0Hz, 1H), 4.65 (q, J = 6.3 Hz, 1H), 3.79 (m, pyrimidinediamine 2H), 2.58(d, J = 4.5 Hz, 3H), 1.43 (d, J = 1297 N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 12.11 (s, 1H), 9.87 (s, 1H), 9.81 (s, 1H), 8.53 + − [4-[N-(N- (m, 1H), 8.20 (d, J = 3.9 Hz, 1H), 7.67-7.78 (m, 6H), 7.54 (dd, J =2.4, methylamino)carbonylmethylene]aminocarbonylphenyl]-2,4- 8.7 Hz,1H), 7.29 (d, J = 9.0 Hz, 1H), 3.79 (d, J = 6.0 Hz, 2H), 2.58 (d,pyrimidinediamine J = 4.2 Hz, 1H); LCMS: purity: 97.8%; MS 1298(R,S)-N4-[4- (N-tert-Butoxycarbonyl)amino-3,4-dihydro-2H-1- LCMS: purity97%; MS (m/e): 566.4 (MH+). + − benzopyran-6-yl]-5-fluoro-N2-[4-[N- (N-methylamino)carbonylmethylene]aminocarbonylphenyl]-2,4-pyrimidinediamine 1299(R,S)-N4-[4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl]-5- LCMS: purity:93.5%; MS (m/e): 466.3 (MH+). + + − + fluoro-N2-[4-[N- (N-methylamino)carbonylmethylene]aminocarbonylphenyl]-2,4-pyrimidinediamine 1300 N4- (3,4-Dichlorophenyl)-5-fluoro-N2-[4-[N- (N-1H NMR (DMSO-d6): d 9.84 (s, 1H), 9.81 (s, 1H), 8.54 (m, 1H), 8.24 + + −methylamino)carbonylmethylene]aminocarbonylphenyl]-2,4- (d, J = 3.9 Hz,1H), 8.10 (d, J = 2.4 Hz, 1H), 7.68-7.81 (m, 6H), 7.56 pyrimidinediamine(d, J = 9.0 Hz, 1H), 3.79 (d, J = 6.0 Hz, 2H), 2.58 (d, J = 3.9 Hz, 3H);LCMS: purity: 100%; MS (m/e): 463.2 (MH+). 1301 N4-(3,4-Dichlorophenyl)-5-fluoro-N4-methyl-N2-[4-[N- (N- 1H NMR (DMSO-d6):d 9.75 (s, 1H), 8.50 (m, 1H), 8.12 (d, J = 4.8 Hz, + + −methylamino)carbonylmethylene]aminocarbonylphenyl]-2,4- 1H), 7.63-7.79(m, 7H), 7.34 (dd, J = 2.4, 9.6 Hz, 1H), 3.78 (d, J = 4.8pyrimidinediamine Hz, 2H), 3.09 (s, 3H), 2.58 (d, J = 4.5 Hz, 3H); LCMS:purity: 94.1%; MS (m/e): 477.2 (MH+). 1302 N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 10.71 (s, 1H), 9.93 (bs, 2H), 8.32 (m, 1H), + + + [4-[N-(2-methoxycarbonylethyl)aminocarbonyl]phenyl]-2,4- 8.19 (d, J = 4.8 Hz,1H), 7.61-7.69 (m, 4H), 7.22-7.25 (m, 2H), 6.94 (d, pyrimidinediamine J= 6.93 Hz, 1H), 3.60 (s, 3H), 3.44 (q, J = 6.9 Hz, 2H), 2.57 (t, J = 6.9Hz, 2H), 1.41 (s, 6H); LCMS: purity: 97.5%; 1303 (S)-5-Fluoro-N2-[4-[N-(2- 1H NMR (DMSO-d6): d 10.83 (s, 1H), 10.32 (s, 1H), 10.13 (s, 1H), + +− methoxycarbonylethyl)aminocarbonyl]phenyl]-N4- (2-methyl-3- 8.39 (m,1H), 8.25 (d, J = 4.8 Hz, 1H), 7.62-7.72 (m, 4H), 7.35 (s, 1H),oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine 7.21 (dd, J = 2.4,8.7 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 4.66 (q, J = 6.9 Hz, 1H), 3.59(s, 3H), 3.43 (m, 2H), 2.57 1304 N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- 1H NMR(DMSO-d6): d 12.15 (s, 1H), 9.85 (m, 2H), 8.31 (m, 1H), 8.20 + + −[4-[N- (2-methoxycarbonylethyl)aminocarbonyl]phenyl]-2,4- (d, J = 4.2Hz, 1H), 7.70-7.78 (m, 5H), 7.50 (d, J = 9.6 Hz, 1H), 7.27pyrimidinediamine (d, J = 9.90 Hz, 1H), 3.59 (s, 3H), 3.42 (m, 2H), 2.56(t, J = 6.9 Hz, 2H); LCMS: purity: 88.5%; MS (m/e): 517.3 (MH 1305 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[4-[N- (2- 1H NMR (DMSO-d6): d 9.82 (s,1H), 9.77 (s, 1H), 8.36 (m, 1H), 8.24 + + +methoxycarbonylethyl)aminocarbonyl]phenyl]-2,4- (d, J = 3.9 Hz, 1H),8.11 (d, J = 2.4 Hz, 1H), 7.65-7.79 (m, 5H), 7.56 pyrimidinediamine (d,J = 8.7 Hz, 1H), 3.60 (s, 3H), 3.47 (q, J = 6,6 Hz, 2H), 2.57 (t, J =6.6 Hz, 1H); purity 90.9%; MS (m/e): 478 1306 N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[4-[N- (2- 1H NMR (DMSO-d6): d 9.94 (s,1H), 8.41 (m, 1H), 8.16 (d, J = 5.7 Hz, + + −methoxycarbonylethyl)aminocarbonyl]phenyl]-N4-methyl-2,4- 1H), 7.64-7.75(m, 6H), 7.36 (dd, J = 2.4, 8.7 Hz, 1H), 3.59 (s, 3H), pyrimidinediamine3.50 (s, 3H), 3.45 (m, 2H), 2.57 (t, J = 7.6 Hz, 2H); LCMS: purity:88.5%; MS (m/e): 492.2 (MH+). 1307 N2-[4-[1- (tert- 1H NMR (DMSO-d6): d10.59 (s, 1H), 9.29 (s, 1H), 9.01 (s, 1H), 8.12 + + +Butoxycarbonylamino)methylenecarbonylamino]methylphenyl]- (m, 1H), 8.03(d, J = 3.6 Hz, 1H), 7.56 (d, J = 9.0 Hz, 2H), 7.27 (dd, J = N4-(2,2-dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4- 2.1, 8.4 Hz,1H), 7.21 (d, J = 2.4 Hz, 1H), 7.05 (d, J = 8.7 Hz, 2H),pyrimidinediamine 6.90 (d, J = 9.0 Hz, 2H), 4.16 (d, J = 5.4 1308(S)-N2-[4-[1- (tert- 1H NMR (DMSO-d6): d 10.63 (s, 1H), 9.29 (s, 1H),9.00 (s, 1H), 8.13 + + +Butoxycarbonylamino)methylenecarbonylamino]methylphenyl]- (m, 1H), 8.03(d, J = 3.6 Hz, 1H), 7.29-7.57 (m, 3H), 7.21 (d, J = 2.1 5-fluoro-N4-(2-methyl-3-oxo-2H,4H-benz[1,4]oxazin-6-yl)-2,4- Hz, 1H), 7.05 (d, J =9.0 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 4.65 (q, J = pyrimidinediamine7.5 Hz, 1H), 4.16 (d, J = 5.7 Hz, 2H), 3 1309 N2-[4-[1- (tert- 1H NMR(DMSO-d6): d 9.52 (s, 1H), 9.08 (s, 1H), 8.13 (m, 1H), 8.09 + + −Butoxycarbonylamino)methylenecarbonylamino]methylphenyl]- (d, J = 3.3Hz, 1H), 7.46-7.62 (m, 4H), 7.23 (d, J = 8.7 Hz, 2H), 7.07 N4-(2,2-difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-2,4- (d, J = 8.4Hz, 2H), 6.92 (m, 1H), 4.18 (d, J = 5.7 Hz, 2H), 3.54 (d, J =pyrimidinediamine 5.7 Hz, 2H), 1.37 (s, 9H); LCMS: purity: 93 1310N2-[4-[1- (tert- 1H NMR (DMSO-d6): d 9.56 (s, 1H), 9.28 (s, 1H),8.12-8.17 (m, 3H), + + +Butoxycarbonylamino)methylenecarbonylamino]methylphenyl]- 7.51-7.81 (m,4H), 7.14 (d, J = 8.7 Hz, 2H), 6.93 (m, 1H), 4.20 (d, J = N4-(3,4-dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine 6.3 Hz, 2H), 3.54(d, J = 6.6 Hz, 2H), 1.38 (s, 9H); LCMS: purity: 94.1%; MS (m/e): 535.3(MH+). 1311 N2-[4-[1- (tert- 1H NMR (DMSO-d6): d 9.31 (s, 1H), 8.15 (m,1H), 8.04 (d, J = 5.4 Hz, + −Butoxycarbonylamino)methylenecarbonylamino]methylphenyl]- 1H), 7.55-7.66(m, 4H), 7.30 (m, 1H), 7.08 (d, J = 8.7 Hz, 2H), 6.94 (m, N4-(3,4-dichlorophenyl)-5-fluoro-N4-methyl-2,4- 1H), 4.18 (d, J = 6.3 Hz,2H), 3.54 (d, J = 6.3 Hz, 2H), 3.46 (s, 3H), pyrimidinediamine 1.38 (s,9H); LCMS: purity: 90.1%; MS (m/e 1312 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- LCMS: ret.time: 3.67 min. (9 min. method); purity: 95.3%; MS (m/e): + + N2-[4-[N-(2-methoxycarbonylethyl)aminocarbonyl]phenyl]-2,4- 496.3 (MH+).pyrimidinediamine 1313 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- LCMS: ret.time: 4.45 min. (9 min. method); purity: 97.3%; MS (m/e): + N2-(4-methoxycarbonylphenyl)-2,4-pyrimidinediamine 439.3 (MH+). 1314 N4-(2,2-Dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro- LCMS: ret.time: 4.00 min. (9 min. method); purity: 95.1%; MS (m/e): + N2-(3-methoxycarbonylppyrid-2yl)-2,4-pyrimidinediamine 440.4 (MH+). 1315N2- (4-Aminocarbonylphenyl)-N4- (2,2-dimethyl-3-oxo-4H-5- LCMS: ret.time: 3.28 min. (9 min. method); purity: 98.1%; MS (m/e): +pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 424.3 (MH+). 1316N2- (2-Aminocarbonylphenyl)-N4- (2,2-dimethyl-3-oxo-4H-5- LCMS: ret.time: 3.98 min. (9 min. method); purity: 90.1%; MS (m/e): + −pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 424.5 (MH+). 1317N4- (2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- LCMS: ret.time: 8.50 min. (20 min. method); purity: 98.8%; MS (m/e):(indazol-6-yl)-2,4-pyrimidinediamine Methanesulfonic Acid Salt 420.1(MH+). 1318 N4-(2,2-Difluoro-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N2- LCMS: ret.time: 9.69 min. (20 min. method); purity: 98.4%; MS (m/e): [3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- 475.3 (MH+).pyrimidinediamine Methanesulfonic Acid Salt 1319 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2- (4-[N- LCMS: ret. time: 3.17min. (7 min. method); purity: 97.5%; MS (m/e): +[methoxycarbonylmethylene]aminocarbonyl]phenyl)-2,4- 460.3 (MH+).pyrimidinediamine 1320 N4- (3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(4-[2-[N,N- LCMS: ret. time: 2.64 min. (7 min. method); purity: 100%; MS(m/e): + + diethylamino]ethyleneaminocarbonyl]phenyl)-2,4- 487.3 (MH+).pyrimidinediamine 1321 N2- (4-Aminocarbonylphenyl)-N4-(3-chloro-4-methoxyphenyl)- LCMS: ret. time: 2.86 min. (7 min. method);purity: 100%; MS (m/e): + + 5-fluoro-2,4-pyrimidinediamine 488.3 (MH+).1322 N4- (3-Chloro-4-methoxyphenyl)-5-fluoro-N2- (4- LCMS: ret. time:4.02 min. (7 min. method); purity: 98.4%; MS (m/e): +methoxycarbonylphenyl)-2,4-pyrimidinediamine 403.3 (MH+). 1323 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2- (4-[N-tert- LCMS: ret. time:3.83 min. (7 min. method); purity: 92.3%; MS (m/e): +butoxycarbonylaminomethylene]phenyl)-2,4-pyrimidinediamine 474.3 (MH+).1324 N2- (4-Aminomethylenephenyl)-N4- (3-chloro-4- LCMS: ret. time: 2.53min. (7 min. method); purity: 96.6%; MS (m/e): +methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 374.2 (MH+). 1325 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2- (4-[N-[N- LCMS: ret. time: 2.81min. (7 min. method); purity: 100%; MS (m/e): +methyl]aminocarbonylmethylene]aminocarbonyl]phenyl)-2,4- 459.3 (MH+).pyrimidinediamine 1326 2-Chloro-5-fluoro-N4- (4-[N- LCMS: ret. time:2.79 min. (7 min. method); purity: 100%; MS (m/e): −[methoxycarbonylmethylene]aminocarbonyl]phenyl)-4- 339.2 (MH+).pyrimidineamine 1327 N4-[4-Aminocarbonylphenyl]-2-chloro-5-fluoro-4-LCMS: ret. time: 2.40 min. (7 min. method); purity: 100%; MS (m/e): −pyrimidineamine 267.1 (MH+). 1328 5-Fluoro-N2- (3-hydroxyphenyl)-N4-(4-[N- LCMS: ret. time: 2.44 min. (7 min. method); purity: 94.9%; MS(m/e): + [methoxycarbonylmethylene]aminocarbonyl]phenyl)-2,4- 412.3(MH+). pyrimidinediamine 1329 N2-(3,5-Dichloro-4-hydroxyphenyl)-5-fluoro-N4- (4-[N- LCMS: ret. time: 9.92min. (20 min. method); purity: 95.0%; MS (m/e): +[methoxycarbonylmethylene]aminocarbonyl]phenyl)-2,4- 482.0 (MH+).pyrimidinediamine 1330 N2- (3-Chloro-4-methoxyphenyl)-5-fluoro-N4-(4-[N- LCMS: ret. time: 3.13 min. (7 min. method); purity: 95% MS(m/e): + + + [methoxycarbonylmethylene]aminocarbonyl]phenyl)-2,4- 460.3(MH+). pyrimidinediamine 1331 N2-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-fluoro-N4- LCMS: ret.time: 2.80 min. (7 min. method); purity: 92.2%; MS (m/e): + +(4-[N-[methoxycarbonylmethylene]aminocarbonyl]phenyl)-2,4- 495.3 (MH+).pyrimidinediamine 1332 5-Fluoro-N2,N4-bis (4-[N- LCMS: ret. time: 2.77min. (7 min. method); purity: 100%; MS (m/e): + +[methoxycarbonylmethylene]aminocarbonyl]phenyl)-2,4- 511.4 (MH+).pyrimidinediamine 1333 N2- (4-Aminocarbonylphenyl)-5-fluoro-N4- (4-[N-LCMS: ret. time: 2.48 min. (7 min. method); purity: 97.6%; MS (m/e): − −[methoxycarbonylmethylene]aminocarbonyl]phenyl)-2,4- 439.3 (MH+).pyrimidinediamine 1334 N4- (4-Aminocarbonylphenyl)-5-fluoro-N2-(3-hydroxyphenyl)- LCMS: ret. time: 2.10 min. (7 min. method); purity:100%; MS (m/e): + + 2,4-pyrimidinediamine 340.2 (MH+). 1335 N4-(4-Aminocarbonylphenyl)-N2- (3,5-dichloro-4- LCMS: ret. time: 8.72 min.(20 min. method); purity: 93.0%; MS (m/e): + +hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine 410.0 (MH+). 1336 N4-(4-Aminocarbonylphenyl)-N2- (3-chloro-4-methoxyphenyl)- LCMS: ret. time:2.79 min. (7 min. method); purity: 100%; MS (m/e): + +5-fluoro-2,4-pyrimidinediamine 388.3 (MH+). 1337 N4-(4-Aminocarbonylphenyl)-N2- (2,2-dimethyl-3-oxo-4H- LCMS: ret. time:2.50 min. (7 min. method); purity: 100%; MS (m/e): + + +benz[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine 423.3 (MH+). 1338N4- (Aminocarbonylphenyl)-5-fluoro-N2- (4-[N- LCMS: ret. time: 2.52 min.(7 min. method); purity: 94.4%; MS (m/e): + +[methoxycarbonylmethylene]aminocarbonyl]phenyl)-2,4- 439.3 (MH+).pyrimidinediamine 1339 N2,N4-Bis (4-aminocarbonylphenyl)-5-fluoro-2,4-LCMS: ret. time: 2.26 min. (7 min. method); purity: 100%; MS (m/e): − −pyrimidinediamine 367.3 (MH+). 1340 N4-(2,2-Dimethyl-3-oxo-4H-N4-oxo-5-pyrido[1,4]oxazin-6-yl)- LCMS: ret.time: 3.48 min. (7 min. method); purity: 97.4%; MS (m/e): + +5-fluoro-N2- (3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 487.3 (MH+).1341 N2- (4-Aminocarbonylphenyl)-5-fluoro-N4- (4-[3-methyl-1,2,4- LCMS:ret. time: 2.72 min. (7 min. method); purity: 95.8%; MS (m/e): + + +oxadiazol-5-yl]methyleneoxyphenyl)-2,4-pyrimidinediamine 436.3 (MH+).1342 5-Fluoro-N2- (4-[N- LCMS: ret. time: 2.99 min. (7 min. method);purity: 95.1%; MS (m/e): + +[methoxycarbonylmethylene]aminocarbonyl]phenyl)-N4- (4-[3- 508.4 (MH+).methyl-1,2,4-oxadiazol-5-yl]methyleneoxyphenyl)-2,4- pyrimidinediamine1343 N2- (4-[2-[N,N-Diethylamino]ethyleneaminocarbonyl]phenyl)-5- LCMS:ret. time: 2.58 min. (7 min. method); purity: 97.8%; MS (m/e): + + +fluoro-N4- (4-[3-methyl-1,2,4-oxadiazol-5- 535.4 (MH+).yl]methyleneoxyphenyl)-2,4-pyrimidinediamine 1344 N2-(3,5-Dichloro-4-hydroxyphenyl)-5-fluoro-N4- (4-[3-methyl- LCMS: ret.time: 3.33 min. (7 min. method); purity: 95.0%; MS (m/e): + − +1,2,4-oxadiazol-5-yl]methyleneoxyphenyl)-2,4- 477.2 (MH+).pyrimidinediamine 1345 N2- (3-Chloro-5-methoxyphenyl)-5-fluoro-N4-(4-[3-methyl- LCMS: ret. time: 3.35 min. (7 min. method); purity: 96.4%;MS (m/e): − + 1,2,4-oxadiazol-5-yl]methyleneoxyphenyl)-2,4- 457.3 (MH+).pyrimidinediamine 1346 N2- (4-Aminocarbonylphenyl)-N4-(3,4-dichlorophenyl)-5-fluoro- LCMS: ret. time: 3.86 min. (7 min.method); purity: 100%; MS (m/e): + N4-methyl-2,4-pyrimidinediamine 406.2(MH+). 1347 N2- (4-[2-[N,N-Diethylamino]ethyleneaminocarbonyl]phenyl)-LCMS: ret. time: 3.31 min. (7 min. method); purity: 100%; MS (m/e): +N4- (3,4-dichlorophenyl)-5-fluoro-N4-methyl-2,4- 505.3 (MH+).pyrimidinediamine 1348 N4- (3,4-Dichlorophenyl)-5-fluoro-N2- (4-[N-LCMS: ret. time: 4.16 min. (7 min. method); purity: 95.8%; MS (m/e): +[methoxycarbonylmethylene]aminocarbonyl]phenyl)-N4- 480.2 (MH+).methyl-2,4-pyrimidinediamine 1349 N2- (4-Aminocarbonylphenyl)-N4-(cyclopentyl)-5-fluoro-2,4- LCMS: ret. time: 2.26 min. (7 min. method);purity: 100%; MS (m/e): − pyrimidinediamine 316.3 (MH+). 1350 N4-(Cyclopentyl)-N2- (4-[2- (N,N- LCMS: ret. time: 2.09 min. (7 min.method); purity: 97.3%; MS (m/e): − +diethylamino]ethyleneaminocarbonyl)phenyl)-5-fluoro-2,4- 415.4 (MH+).pyrimidinediamine 1351 N4- (Cyclopentyl)-5-fluoro-N2- (4-[N- LCMS: ret.time: 2.62 min. (7 min. method); purity: 100%; MS (m/e): + +[methoxycarbonylmethylene]aminocarbonyl]phenyl)-2,4- 388.3 (MH+).pyrimidinediamine 1352 N2- (4-Aminocarbonylphenyl)-N4-(4-chloro-3-methoxyphenyl)- LCMS: ret. time: 3.13 min. (7 min. method);purity: 96.4%; MS (m/e): + 5-fluoro-2,4-pyrimidinediamine 388.3 (MH+).1353 N2- (4-Aminocarbonyl-3-chlorophenyl)-N4- (3-chloro-4- LCMS: ret.time: 2.91 min. (7 min. method); purity: 89.5%; MS (m/e): + +methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 422.2 (MH+). 1354 N2-(4-Aminocarbonyl-3-chlorophenyl)-N4- (4-chloro-3- LCMS: ret. time: 3.14min. (7 min. method); purity: 95.0%; MS (m/e): + +methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 422.2 (MH+). 1355 N4-(4-Chloro-3-methoxyphenyl)-N2- (4-[2-[N,N- LCMS: ret. time: 2.80 min. (7min. method); purity: 95.6%; MS (m/e): + +diethylamino]ethyleneaminocarbonyl]phenyl)-5-fluoro-2,4- 487.4 (MH+).pyrimidinediamine 1356 N4- (4-Chloro-3-methoxyphenyl)-5-fluoro-N2-(4-[N- LCMS: ret. time: 3.45 min. (7 min. method); purity: 94.6%; MS(m/e): + + [methoxycarbonylmethylene]aminocarbonyl]phenyl)-2,4- 460.3(MH+). pyrimidinediamine 1357 N2-(4-Aminocarbonylphenyl)-5-fluoro-N4-phenyl-2,4- LCMS: ret. time: 2.58min. (7 min. method); purity: 100%; MS (m/e): + + pyrimidinediamine424.3 (MH+). 1358 5-Fluoro-N2- (3-hydroxyphenyl)-N4- (4-[3-methyl-1,2,4-LCMS: ret. time: 2.72 min. (7 min. method); purity: 89.9%; MS (m/e):oxadiazol-5-yl]methyleneoxyphenyl)-2,4-pyrimidinediamine 409.3 (MH+).hydrochloric acid salt

7.5 The Compounds Are Effective for the Treatment of Autoimmunity

The in vivo efficacy of certain 2,4-pyrimidinediamine compounds towardsautoimmune diseases was evaluated in the reverse passive Arthusreaction, an acute model of antigen-antibody mediated tissue injury, andin several disease models of autoimmunity and inflammation. These modelsare similar in that antibody to a specific antigen mediates immunecomplex-triggered (IC-triggered) inflammatory disease and subsequenttissue destruction. IC deposition at specific anatomic sites (centralnervous system (CNS) for experimental autoimmune encephalomyelitis (EAE)and synovium for collagen-induced arthritis (CIA)) leads to activationof cells expressing surface FcγR and FcεR, notably mast cells,macrophages, and neutrophils, which results in cytokine release, andneutrophil chemotaxis. Activation of the inflammatory response isresponsible for downstream effector responses, including edema,hemorrhage, neutrophil infiltration, and release of pro-inflammatorymediators. The consequences of these IC-triggered events are difficultto identify in autoimmune disorders; nonetheless, many investigatorshave demonstrated that inhibition of the FcγR signaling pathway in theseanimal models has resulted in a significant reduction in disease onsetand severity.

7.5.1 the Compounds are Effective in Mouse Arthus Reaction

The in vivo efficacy of compounds 810, 944, 994 and 1007 to inhibit theIC-triggered inflammatory cascade was demonstrated in a mouse model ofReverse Passive Arthus Reaction (RPA reaction).

7.5.1.1 Model

Immune complex (IC)-mediated acute inflammatory tissue injury isimplicated in a variety of human autoimmune diseases, includingvasculitis syndrome, sick serum syndrome, systemic lupus erythematosus(SLE), rheumatoid arthritis, Goodpasture's syndrome, andglomerulonephritis. The classical experimental model for IC-mediatedtissue injury is the reverse passive Arthus reaction. The RPA reactionmodel is a convenient in vivo method to study localized inflammation,induced by ICs, without systemic effects. Intradermal injection ofantibodies (Abs) specific to chicken egg albumin (rabbit anti-OVA IgG),followed by intravenous (IV) injection of antigens (Ags), specificallychicken egg albumin (ovalbumin, OVA), causes perivascular deposition ofICs and a rapid inflammatory response characterized by edema, neutrophilinfiltration and hemorrhage at the injection sites. Aspects of the mouseRPA reaction model resemble the inflammatory response of patients withrheumatoid arthritis, SLE and glomerulonephritis.

7.5.1.2 Study Protocol

In this model system, test compounds are administered at severaltimepoints prior to administration of Abs and Ags. A solution of rabbitanti-OVA IgG (50 μM in 25 μl/mouse) is injected intradermally, andimmediately following is an intravenous injection of chicken egg albumin(20 mg/kg of body weight) in a solution containing 1% Evans blue dye.The degree of edema and hemorrhage is measured in the dorsal skin ofC57BL/6 mice using the Evan's Blue dye as an indicator of local tissuedamage. Purified polyclonal rabbit IgG is used as a control.

Pretreatment time, in which the test compounds are administered prior toAb/Ag challenge, depends on the pharmacokinetic (PK) properties of eachindividual compound. Four hours after induction of Arthus reaction, miceare euthanized, and tissues are harvested for assessment of edema. Thismodel system allows us to rapidly screen the in vivo activity of manyinhibitors.

7.5.1.3 Results

All compounds tested were administered by the oral route.

Compound 994, when administered at a dose level of 100 mg/kg 90 minutesprior to Ab/Ag challenge in C57B16 mice, showed dose-dependentinhibition of edema formation (75%).

Compounds 1007 and 810 showed the efficacy of edema inhibition by 89.4%and 81.3%, respectively, when administered at 1.0 mg/kg, 30 minutesprior to challenge.

Compound 1007 showed 64.3%, 78.7%, 98.1% and 99.8%, inhibition of edemaformation when administered at dose levels of 0.1 mg/kg, 0.5 mg/kg, 1.0mg/kg and 5 mg/kg and a pretreatment time of 30, respectively. Resultsfor the compounds tested are summarized in Table 2.

TABLE 2 Mouse Cutaneous Reverse Passive Arthus (RPA) Reaction Summary invitro % inhibition Satellite: At Exposure = Potency to vehicle time ofchall- Pretreatment (CHMC control enge Plasma Time + 4 hours IgE)Compound Compound Dosage Pretreatment Edema Concentration ± PlasmaConcentration ± Name Number (mg/kg) Time (hrs) Size ± SEM SEM (ng/ml)SEM (ng/ml) 994 100 75.0 ± 6.2 78.6 ± 26.4 44.2 ± 8.9  0.047 1007 1 0.589.4 ± 2.2 3 0.5 86.3 ± 7.9 10 0.5 97.8 ± 1.1 30 0.5 88.2 ± 5.7 1007 0.10.5  64.3 ± 11.2 24.4 ± 9.6  BLQ 0.5 0.5 78.7 ± 6.3 73.1 ± 14.5 BLQ 10.5 98.1 ± 0.8 90.0 ± 11.0 2.3 ± 0.9 5 0.5 99.8 ± 0.2 398.0 ± 30.2  19.8± 15.7 810 0.1 0.5  69.5 ± 19.6 0.5 0.5 60.9 ± 9.6 1 0.5 81.3 ± 8.4 50.5 92.1 ± 3.1 944 2 1  39.3 ± 13.8 NA 4.3 ± 4.2 5 1  48.4 ± 12.0 NA 3.5± 5.3 15 1 56.1 ± 9.2 NA 29.7 ± 25.9 944 0.5 5 −16.0 ± 17.3 22.1 ± 52.43.4 ± 9.1 0.5 15  8.3 ± 13.4 1074.0 ± 492.3   85.1 ± 161.9

7.5.2 the Compounds are Effective in Mouse Collagen Antibody InducedArthritis Model

The in vivo efficacy of compounds towards autoimmune diseases can bedemonstrated in a mouse model of collagen antibody-induced arthritis(CAIA).

7.5.2.1 Model

Collagen-induced arthritis (CIA) in rodents is frequently used as one ofthe experimental models for IC-mediated tissue injury. Administration oftype II collagen into mice or rats results in an immune reaction thatcharacteristically involves inflammatory destruction of cartilage andbone of the distal joints with concomitant swelling of surroundingtissues. CIA is commonly used to evaluate compounds that might be ofpotential use as drugs for treatment of rheumatoid arthritis and otherchronic inflammatory conditions.

In recent years, a new technique emerged in CIA modeling, in which theanti-type II collagen antibodies are applied to induce anantibody-mediated CIA. The advantages of the method are: Short time forinduction of disease (developing within 24-48 hrs after an intravenous(IV) injection of antibodies); arthritis is inducible in bothCIA-susceptible and CIA-resistant mouse strains; and the procedure isideal for rapid screening of anti-inflammatory therapeutic agents.

Arthrogen-CIA® Arthritis-inducing Monoclonal Antibody Cocktail (ChemiconInternational Inc.) is administered intravenously to Balb/c mice (2mg/mouse) on Day 0. Forty-eight hours later, 100 μl of LPS (25 μg) isinjected intraperitoneally. On Day 4, toes may appear swollen. By Day 5,one or two paws (particular the hind legs) begin to appear red andswollen. On Day 6, and thereafter, red and swollen paws will remain forat least 1-2 weeks. During the study, the clinical signs of inflammationare scored to evaluate the intensity of edema in the paws. The severityof arthritis is recorded as the sum score of both hind paws for eachanimal (possible maximum score of 8). The degree of inflammation withinvolved paws is evaluated by measurement of diameter of the paws. Bodyweight changes are monitored.

Animals can be treated at the time of induction of arthritis, beginningon Day 0. Test compounds and control compounds can be administered oncea day (q.d.) or twice a day (b.i.d.), via per os (PO), depending onpreviously established PK profiles.

At the end of the study (1-2 weeks after induction of arthritis), miceare euthanized and the paws are transected at the distal tibia using aguillotine and weighed. The mean±standard error of the mean (SEM) foreach group is determined each day from individual animal clinicalscores, and hind paw weights for each experimental group are calculatedand recorded at study termination. Histopathological evaluation of pawsare obtained.

7.5.2.2 Results

Reduced inflammation and swelling should be evident in animals treatedwith compounds of the invention, and the arthritis would progress moreslowly. Treatment with compounds should (b.i.d.) significantly reduceclinical arthritis compared with animals treated with vehicle only.

7.5.3 The Compounds Can Be Effective In Rat Collagen-Induced Arthritis

The in vivo efficacy of compounds of the invention towards autoimmunediseases can be demonstrated in a rat model of collagen-inducedarthritis (CIA).

7.5.3.1 Model Description

Rheumatoid arthritis (RA) is characterized by chronic joint inflammationeventually leading to irreversible cartilage destruction. IgG-containingIC are abundant in the synovial tissue of patients with RA. While it isstill debated what role these complexes play in the etiology andpathology of the disease, IC communicate with the hematopoetic cells viathe FcγR.

CIA is a widely accepted animal model of RA that results in chronicinflammatory synovitis characterized by pannus formation and jointdegradation. In this model, intradermal immunization with native type IIcollagen, emulsified with incomplete Freund's adjuvant, results in aninflammatory polyarthritis within 10 or 11 days and subsequent jointdestruction in 3 to 4 weeks.

7.5.3.2 Study Protocol

Syngeneic LOU rats were immunized on Day 0 with native chicken CII/IFA(performed at UCLA; E. Brahn, Principal Investigator). Beginning on theday of arthritis onset (Day 10), a total of 59 rats can be treated witheither a vehicle control or a compound of the invention at one of fourdose levels (1, 3, 10, and 30 mg/kg, q.d. by p.o. gavage).

7.5.3.3 Results

Hind limbs would be scored daily for clinical arthritis severity using astandardized method based on the degree of joint inflammation. Highresolution digital radiographs of hind limbs can be obtained at theconclusion of the study (Day 28). These limbs can also be analyzed forhistopathologic changes. IgG antibodies to native CII can be measured inquadruplicate by ELISA.

Although the foregoing invention has been described in some detail tofacilitate understanding, it will be apparent that certain changes andmodifications may be practiced within the scope of the appended claims.Accordingly, the described embodiments are to be considered asillustrative and not restrictive, and the invention is not to be limitedto the details given herein, but may be modified within the scope andequivalents of the appended claims.

All literature and patent references cited throughout the applicationare incorporated by reference into the application for all purposes.

We claim:
 1. A compound of the formula (I):

wherein: L¹ and L² are each, independently of one another, selected fromthe group consisting of a direct bond and a linker selected from (C1-C6)alkyldiyl, (C1-C6) alkano or (C1-C6) heteroalkyldiyl; R² is a phenylgroup trisubstituted with three R^(b) groups; R⁴ is

R⁵ is selected from the group consisting of R⁶, (C1-C6) alkyl optionallysubstituted with one or more of the same or different R⁸ groups, (C1-C4)alkanyl optionally substituted with one or more of the same or differentR⁸ groups, (C2-C4) alkenyl optionally substituted with one or more ofthe same or different R⁸ groups and (C2-C4) alkynyl optionallysubstituted with one or more of the same or different R⁸ groups; each R⁶independently is selected from the group consisting of hydrogen, anelectronegative group, —OR^(d), —SR^(d), (C1-C3) haloalkyloxy, (C1-C3)perhaloalkyloxy, —NR^(c)R^(c), halogen, (C1-C3) haloalkyl,(C1-C3)perhaloalkyl, —CF₃, —CH₂CF₃, —CF₂CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂,—N₃, —S(O)R^(d), —S(O)₂R^(d), —S(O)₂OR^(d), —S(O)NR^(c)R^(c),—S(O)₂NR^(c)R^(c), —OS(O)R^(d), —OS(O)₂R^(d), —OS(O)₂OR^(d),—OS(O)NR^(c)R^(c), —OS(O)₂NR^(c)R^(c), —C(O)R^(d), —C(O)OR^(d),—C(O)NR^(c)R^(c), —C(NH)NR^(c)R^(c), —OC(O)R^(d), —SC(O)R^(d),—OC(O)OR^(d), —SC(O)OR^(d), —OC(O)NR^(c)R^(c), —SC(O)NR^(c)R^(c),—OC(NH)NR^(c)R^(c), —SC(NH)NR^(c)R^(c), —[NHC(O)]_(n)R^(d),—[NHC(O)]_(n)OR^(d), —[NHC(O)]_(n)NR^(c)R^(c) and—[NHC(NH)]_(n)NR^(c)R^(c), (C5-C10) aryl optionally substituted with oneor more of the same or different R⁸ groups, phenyl optionallysubstituted with one or more of the same or different R⁸ groups,(C6-C16) arylalkyl optionally substituted with one or more of the sameor different R⁸ groups, 5-10 membered heteroaryl optionally substitutedwith one or more of the same or different R⁸ groups and 6-16 memberedheteroarylalkyl optionally substituted with one or more of the same ordifferent R⁸ groups; R⁸ is selected from the group consisting of R^(a),R^(b), R^(a) substituted with one or more of the same or different R^(a)or R^(b), —OR^(a) substituted with one or more of the same or differentR^(a) or R^(b), —B(OR^(a))₂, —B(NR^(c)R^(c))₂, —(CH₂)_(m)—R^(b),—(CHR^(a))_(m)—R^(b), —O—(CH₂)_(m)—R^(b), —S—(CH₂)_(m)—R^(b),—O—CHR^(a)R^(b), —O—CR^(a)(R^(b))₂, —O—(CHR^(a))_(m)—R^(b),—O—(CH₂)_(m)CH[(CH₂)_(m)R^(b)]R^(b), —S—(CHR^(a))_(m)—R^(b),—C(O)NH—(CH₂)_(m)—R^(b), —C(O)NH—(CHR^(a))_(m)—R^(b),—O—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b),—S—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b),—O—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b),—S—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b), —NH—(CH₂)_(m)—R^(b),—NH—(CHR^(a))_(m)—R^(b), —NH—[(CH₂)_(m)R^(b)], —NH—(CH₂)_(m)—R^(b),—NH—C(O)—NH—(CH₂)_(m)—R^(b), —NH—C(O)—(CH₂)_(m)—CHR^(b)R^(b) and—NH—(CH₂)_(m)—C(O)—NH—(CH₂)_(m)—R^(b); each R^(a) is independentlyselected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8)cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl,(C6-C16) arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 memberedcycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl,piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 memberedheteroaryl and 6-16 membered heteroarylalkyl; each R^(b) isindependently selected from —OR^(d), (C₁-C₃)haloalkyloxy, —OCF₃,—SR^(d), —NR^(c)R^(c), halogen, —CF₃, —CN, —S(O)R^(d), —S(O)₂R^(d),—S(O)₂OR^(d), —S(O)NR^(c)R^(c), —S(O)₂NR^(c)R^(c), —OS(O)R^(d),—OS(O)₂R^(d), —C(O)R^(d), —C(O)OR^(d), —C(O)NR^(c)R^(c),—C(NR^(a))NR^(c)R^(c), —OC(O)R^(d), —OC(O)OR^(d), —OC(O)NR^(c)R^(c),—OC(NH)NR^(c)R^(c), —OC(NR^(a))NR^(c)R^(c), —[NHC(O)]_(n)R^(d),—[NR^(a)C(O)]_(n)R^(d), —[NHC(O)]_(n)OR^(d), [NR^(a)C(O)]_(n)OR^(d),—[NHC(O)]_(n)NR^(c)R^(c), and —[NR^(a)C(O)]_(n)NR^(c)R^(c); each R^(c)is independently (C1-C6) alkyl, or, alternatively, each R^(c) is takentogether with the nitrogen atom to which it is bonded to form a 5 to8-membered cycloheteroalkyl each R^(d) is independently (C1-C6) alkyl; Yis O; Z is NH; and X is N; wherein the compound is notN2-(3-Chloro-4-methoxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine;N2-(3-Chloro-4-hydroxy-5-methylphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine;orN2-(3,5-Dimethyl-4-methoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.2. The compound according to claim 1, wherein the substitution about theR² phenyl is at the 2,3,4, 2,3,5, 2,3,6, 2,4,5, 2,4,6, 2,5,6, 3,4,5,3,4,6, 3,5,6, or 4,5,6 positions.
 3. The compound according to claim 1,wherein the substitution about the R² phenyl is at the 2,3,4.
 4. Thecompound according to claim 1, wherein R² is

and each R³¹, independently of the others, is (C1-C6) alkyl.
 5. Thecompound according to claim 1, wherein R⁵ is halogen.
 6. The compoundaccording to claim 1, wherein R⁵ is F.
 7. The compound according toclaim 1, wherein R⁶ is hydrogen.
 8. The compound according to claim 1,wherein L¹ and L² are each a direct bond.
 9. The compound according toclaim 1, wherein L¹ and L² are each (C1-C6) alkyldiyl.
 10. The compoundof claim 1, wherein the compound is in the form of a salt.
 11. Apharmaceutical composition comprising a compound according to claim 1and a pharmaceutically acceptable excipient.
 12. A method of treating anautoimmune diseases or symptom thereof in a patient in need of suchtreatment, the method comprising administering to the patient atherapeutically effective amount of a compound according to claim
 1. 13.The method of claim 12, wherein the disease is a Type II, Type IIIand/or Type IV nonanaphylactic hypersensitivity reaction.
 14. The methodof claim 12, wherein the disease is mediated, at least in part, byactivation of the FcγR signaling cascade in monocyte cells.
 15. Themethod of claim 12, wherein the disease is selected from the groupconsisting of Hashimoto's thyroiditis, autoimmune hemolytic anemia,autoimmune atrophic gastritis of pernicious anemia, autoimmuneencephalomyelitis, autoimmune orchitis, Goodpasture's disease,autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis,Graves' disease, primary biliary cirrhosis, chronic aggressivehepatitis, ulcerative colitis and membranous glomerulopathy.
 16. Themethod of claim 12, wherein the disease is selected from the groupconsisting of systemic lupus erythematosis, Sjogren's syndrome, Reiter'ssyndrome, polymyositis-dermatomyositis, systemic sclerosis,polyarteritis nodosa, multiple sclerosis and bullous pemphigoid.
 17. Themethod of claim 12, wherein the disease is autoimmune hemolytic anemia.18. The method of claim 12, wherein the disease is autoimmunethrombocytopenia.